|
1
|
Cao H, Tao Y, Jin R, Li P, Zhou H, Cheng J. Proteomics reveals the key transcription-related factors mediating obstructive nephropathy in pediatric patients and mice. Ren Fail 2025; 47:2443032. [PMID: 39743726 DOI: 10.1080/0886022x.2024.2443032] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2024] [Revised: 12/05/2024] [Accepted: 12/11/2024] [Indexed: 01/04/2025] Open
Abstract
BACKGROUND Obstructive nephropathy is one of the leading causes of kidney injury in infants and children. Increasing evidence has shown that transcription-related factors (TRFs), including transcription factors and cofactors, are associated with kidney diseases. However, a global landscape of dysregulated TRFs in pediatric patients with obstructive nephropathy is lacking. METHODS We mined the data from our previous proteomic study for the TRF profile in pediatric patients with obstructive nephropathy and unilateral ureteral obstruction (UUO) mice. Gene ontology (GO) analysis was performed to determine pathways that were enriched in the dysregulated TRFs. We then took advantage of kidney samples from patients and UUO mice to verify the selected TRFs by immunoblots. RESULTS The proteomes identified a total of 140 human TRFs with 28 upregulated and 1 downregulated, and 160 murine TRFs with 88 upregulated and 1 downregulated (fold change >2 or <0.5). These dysregulated TRFs were enriched in the inflammatory signalings, such as janus kinase/signal transducer and activator of transcription (JAK-STAT) and tumor necrosis factor (TNF) pathways. Of note, the transforming growth factor (TGF)-β signaling pathway, which is the master regulator of organ fibrosis, was enriched in both patients and mice. Cross-species analysis showed 16 key TRFs that might mediate obstructive nephropathy in patients and UUO mice. Moreover, we verified a significant dysregulation of three previously unexplored TRFs; prohibitin (PHB), regulatory factor X 1 (RFX1), and activity-dependent neuroprotector homeobox protein (ADNP), in patients and mice. CONCLUSIONS Our study uncovered key TRFs in the obstructed kidneys and provided additional molecular insights into obstructive nephropathy.
Collapse
Affiliation(s)
- Hualin Cao
- Department of Urology, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Yuandong Tao
- Department of Pediatric Urology, The Seventh Medical Center of Chinese PLA General Hospital, Beijing, China
- National Engineering Laboratory for Birth Defects Prevention and Control of Key Technology, Beijing, China
| | - Ruyue Jin
- Department of Pediatric Urology, The Seventh Medical Center of Chinese PLA General Hospital, Beijing, China
- National Engineering Laboratory for Birth Defects Prevention and Control of Key Technology, Beijing, China
| | - Pin Li
- Department of Pediatric Urology, The Seventh Medical Center of Chinese PLA General Hospital, Beijing, China
- National Engineering Laboratory for Birth Defects Prevention and Control of Key Technology, Beijing, China
| | - Huixia Zhou
- Department of Pediatric Urology, The Seventh Medical Center of Chinese PLA General Hospital, Beijing, China
- National Engineering Laboratory for Birth Defects Prevention and Control of Key Technology, Beijing, China
| | - Jiwen Cheng
- Department of Urology, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
| |
Collapse
|
|
2
|
Seasock MJ, Shafiquzzaman M, Ruiz-Echartea ME, Kanchi RS, Tran BT, Simon LM, Meyer MD, Erice PA, Lotlikar SL, Wenlock SC, Ochsner SA, Enright A, Carisey AF, Romero F, Rosas IO, King KY, McKenna NJ, Coarfa C, Rodriguez A. Let-7 restrains an oncogenic circuit in AT2 cells to prevent fibrogenic cell intermediates in pulmonary fibrosis. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2024.05.22.595205. [PMID: 38826218 PMCID: PMC11142151 DOI: 10.1101/2024.05.22.595205] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 06/04/2024]
Abstract
Analysis of lung alveolar type 2 (AT2) progenitor stem cells has highlighted fundamental mechanisms that direct their differentiation into alveolar type 1 cells (AT1s) in lung repair and disease. However, microRNA (miRNA) mediated post-transcriptional mechanisms which govern this nexus remain understudied. We show here that the let-7 miRNA family serves a homeostatic role in governance of AT2 quiescence, specifically by preventing the uncontrolled accumulation of AT2 transitional cells and by promoting AT1 differentiation. Using mice and organoid models, we demonstrate genetic ablation of let-7a1/let-7f1/let-7d cluster (let-7afd) in AT2 cells prevents AT1 differentiation and results in accumulation of AT2 transitional cells in progressive pulmonary fibrosis. Integration of AGO2-eCLIP with RNA-sequencing from AT2 cells uncovered the induction of direct targets of let-7 in an oncogene feed-forward regulatory network including BACH1/EZH2/MYC which drives an aberrant fibrotic cascade. Additional analyses using CUT&RUN-sequencing revealed an epigenetic role of let-7 in induction of chromatin histone acetylation and methylation and maladaptive AT2 cell reprogramming. This study identifies let-7 as a key gatekeeper of post-transcriptional and epigenetic chromatin signals to prevent AT2-driven pulmonary fibrosis.
Collapse
Affiliation(s)
- Matthew J Seasock
- Immunology & Microbiology Graduate Program, Baylor College of Medicine, Houston, TX, 77030
- Department of Medicine, Section of Immunology, Allergy & Rheumatology, Baylor College of Medicine Houston TX, 77030
| | - Md Shafiquzzaman
- Department of Medicine, Section of Immunology, Allergy & Rheumatology, Baylor College of Medicine Houston TX, 77030
| | - Maria E Ruiz-Echartea
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, 77030
| | - Rupa S Kanchi
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, 77030
- Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine Houston, TX, 77030
| | - Brandon T Tran
- Graduate Program of Cancer Biology and Cell Biology, Baylor College of Medicine, Houston, TX, 77030
- Department of Pediatrics, Division of Infectious Diseases, Texas Children's Hospital, Baylor College of Medicine, Houston, TX, 77030
| | - Lukas M Simon
- Therapeutic Innovation Center, Baylor College of Medicine, Houston, TX, 77030
| | - Matthew D Meyer
- Shared Equipment Authority, Rice University, Houston, TX 77005
| | - Phillip A Erice
- Immunology & Microbiology Graduate Program, Baylor College of Medicine, Houston, TX, 77030
- Department of Medicine, Section of Immunology, Allergy & Rheumatology, Baylor College of Medicine Houston TX, 77030
| | - Shivani L Lotlikar
- Department of Medicine, Section of Immunology, Allergy & Rheumatology, Baylor College of Medicine Houston TX, 77030
| | | | - Scott A Ochsner
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, 77030
| | - Anton Enright
- Department of Pathology, University of Cambridge, Cambridge, CB2 1TN, UK
| | - Alex F Carisey
- William T. Shearer Center for Immunobiology, Texas Children's Hospital, Houston, TX, 77030
- Current Address: Department of Cell and Molecular Biology, St. Jude Children's Research Hospital, Memphis, TN
| | - Freddy Romero
- Department of Medicine, Section of Pulmonary and Critical Care, Baylor College of Medicine. Houston, TX, 77030
- Current Address: Vertex Pharmaceuticals, 3215 Merryfield Row, San Diego, CA, 92121
| | - Ivan O Rosas
- Department of Medicine, Section of Pulmonary and Critical Care, Baylor College of Medicine. Houston, TX, 77030
| | - Katherine Y King
- Department of Pediatrics, Division of Infectious Diseases, Texas Children's Hospital, Baylor College of Medicine, Houston, TX, 77030
| | - Neil J McKenna
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, 77030
| | - Cristian Coarfa
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, 77030
- Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine Houston, TX, 77030
| | - Antony Rodriguez
- Department of Medicine, Section of Immunology, Allergy & Rheumatology, Baylor College of Medicine Houston TX, 77030
- Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine Houston, TX, 77030
- Center for Translational Research on Inflammatory Diseases, Michael E. Debakey, Baylor College of Medicine, Houston, TX, 77030
| |
Collapse
|
|
3
|
Zhu WY, Li X, Xie JL, Lu Q, Ma YJ, Zhu ZJ, Liu J. Hotspots and trends in stem cell therapy for liver fibrosis and cirrhosis: A bibliometric analysis. World J Hepatol 2025; 17:96105. [PMID: 39871895 PMCID: PMC11736489 DOI: 10.4254/wjh.v17.i1.96105] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/01/2024] [Revised: 10/29/2024] [Accepted: 11/19/2024] [Indexed: 01/06/2025] Open
Abstract
BACKGROUND Liver fibrosis and cirrhosis are global medical challenges that require safe and effective treatments. In the past two decades, there has been a surge in research on stem cell therapy for liver fibrosis and cirrhosis. This study aimed to conduct a comprehensive analysis of the research hotspots and trends in this field through bibliometrics. AIM To conduct a bibliometric analysis on hotspots and trends in stem cell therapy for treatment of liver fibrosis and cirrhosis. METHODS Publications on stem cell therapy for liver fibrosis and cirrhosis were retrieved from the Web of Science Core Collection database. The distribution and collaboration among literature, authors, countries, and institutions were analyzed visually using Excel, CiteSpace, Bibliometrix R-package, VOSviewer and Pajek software. Additionally, an investigation of keywords, burst keywords, and clusters was conducted. RESULTS As of September 20, 2024, a total of 1935 documents were retrieved dating from 2004 to 2024, with 1186 strongly relevant publications obtained after screening. China, the United States, and Japan were the major contributors in this field. Cairo University, Zhejiang University and Yamaguchi University were the major institution in this field. The journal Stem Cell Research & Therapy published the most papers. There were 686 authors, with Shuji Terai, Isao Sakaida, Soon Koo Baik, and Lanjuan Li publishing the most papers. The research focused on alcoholic cirrhosis and nonalcoholic fatty liver disease. The emerging areas of interest were extracellular vesicles, exosomes, and their enriched microRNAs. The field is experiencing rapid growth due to the changing research trends and increasing literature. CONCLUSION These findings provide a thorough overview of stem cell therapy in the field of liver fibrosis and cirrhosis.
Collapse
Affiliation(s)
- Wen-Yan Zhu
- Chongqing Engineering Research Center of Pharmaceutical Sciences, Chongqing Medical and Pharmaceutical College, Chongqing 401331, China
- College of Pharmacy, Chongqing Medical University, Chongqing 400016, China
| | - Xiang Li
- Department of Cardiology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
| | - Jia-Ling Xie
- Immunology Research Center of Medical Research Institute, Southwest University, Chongqing 402460, China
| | - Qin Lu
- Immunology Research Center of Medical Research Institute, Southwest University, Chongqing 402460, China
| | - Ying-Jie Ma
- Office of Scientific Research of Army Medical Center, Army Medical University, Chongqing 400042, China
| | - Zhao-Jing Zhu
- Chongqing Engineering Research Center of Pharmaceutical Sciences, Chongqing Medical and Pharmaceutical College, Chongqing 401331, China
| | - Juan Liu
- Immunology Research Center of Medical Research Institute, Southwest University, Chongqing 402460, China.
| |
Collapse
|
|
4
|
Zou X, Brigstock D. Extracellular Vesicles from Mesenchymal Stem Cells: Potential as Therapeutics in Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD). Biomedicines 2024; 12:2848. [PMID: 39767754 PMCID: PMC11673942 DOI: 10.3390/biomedicines12122848] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2024] [Revised: 12/06/2024] [Accepted: 12/12/2024] [Indexed: 01/03/2025] Open
Abstract
Background/Objectives: Metabolic dysfunction-associated steatotic liver disease (MASLD) is characterized by the accumulation of triglycerides within hepatocytes, which can progress to more severe conditions, such as metabolic dysfunction-associated steatohepatitis (MASH), which may include progressive fibrosis, leading to cirrhosis, cancer, and death. This goal of this review is to highlight recent research showing the potential of mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) in reducing the key pathogenic pathways of MASLD or MASH. Methods: Relevant published studies were identified using PubMed with one or more of the following search terms: MASLD, MASH, NAFLD, NASH, exosome, extracellular vesicle (EV), therapy, and/or mesenchymal stem cells (MSC). The primary literature were subsequently downloaded and summarized. Results: Using in vitro or in vivo models, MSC-EVs have been found to counteract oxidative stress, a significant contributor to liver injury in MASH, and to suppress disease progression, including steatosis, inflammation, and, in a few instances, fibrosis. Some of these outcomes have been attributed to specific EV cargo components including microRNAs and proteins. Thus, MSC-EVs enriched with these types of molecules may have improved the therapeutic efficacy for MASLD/MASH and represent a novel approach to potentially halt or reverse the disease process. Conclusions: MSC-EVs are attractive therapeutic agents for treating MASLD/MASH. Further studies are necessary to validate the clinical applicability and efficacy of MSC-EVs in human MASH patients, focusing on optimizing delivery strategies and identifying the pathogenic pathways that are targeted by specific EV components.
Collapse
Affiliation(s)
- Xue Zou
- Center for Clinical and Translational Research, The Abigail Wexner Research Institute at Nationwide Children’s Hospital, Columbus, OH 43205, USA;
| | - David Brigstock
- Center for Clinical and Translational Research, The Abigail Wexner Research Institute at Nationwide Children’s Hospital, Columbus, OH 43205, USA;
- Department of Surgery, Wexner Medical Center, The Ohio State University, Columbus, OH 43212, USA
| |
Collapse
|
|
5
|
Liu N, Wang S, Li M, Zhao N, Wang D, Zhang R, Yu M, Zhao L, Zhang S, Han F, Zhao Y, Liu Q. BET degrader exhibits lower antiproliferative activity than its inhibitor via EGR1 recruiting septins to promote E2F1-3 transcription in triple-negative breast cancer. Pharmacol Res 2024; 208:107377. [PMID: 39209080 DOI: 10.1016/j.phrs.2024.107377] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/18/2024] [Revised: 08/14/2024] [Accepted: 08/23/2024] [Indexed: 09/04/2024]
Abstract
The bromodomain and extraterminal domain (BET) family proteins serve as primary readers of acetylated lysine residues and play crucial roles in cell proliferation and differentiation. Dysregulation of BET proteins has been implicated in tumorigenesis, making them important therapeutic targets. BET-bromodomain (BD) inhibitors and BET-targeting degraders have been developed to inhibit BET proteins. In this study, we found that the BET inhibitor MS645 exhibited superior antiproliferative activity than BET degraders including ARV771, AT1, MZ1 and dBET1 in triple-negative breast cancer (TNBC) cells. Treatment with MS645 led to the dissociation of BETs, MED1 and RNA polymerase II from the E2F1-3 promoter, resulting in the suppression of E2F1-3 transcription and subsequent inhibition of cell growth in TNBC. In contrast, while ARV771 displaced BET proteins from chromatin, it did not significantly alter E2F1-3 expression. Mechanistically, ARV771 induced BRD4 depletion at protein level, which markedly increased EGR1 expression. This elevation of EGR1 subsequently recruited septin 2 and septin 9 to E2F1-3 promoters, enhancing E2F1-3 transcription and promoting cell proliferation rate in vitro and in vivo. Our findings provide valuable insights into differential mechanisms of BET inhibition and highlight potential of developing BET-targeting molecules as therapeutic strategies for TNBC.
Collapse
Affiliation(s)
- Nan Liu
- Department of Infectious Diseases and Center of Infectious Diseases and Pathogen Biology, Key Laboratory of Organ Regeneration and Transplantation of the Ministry of Education, The First Hospital of Jilin University, Changchun 130061, China.
| | - Shuai Wang
- Bethune Institute of Epigenetic Medicine, The First Hospital of Jilin University, Changchun 130061, China
| | - Munan Li
- Bethune Institute of Epigenetic Medicine, The First Hospital of Jilin University, Changchun 130061, China
| | - Nan Zhao
- Bethune Institute of Epigenetic Medicine, The First Hospital of Jilin University, Changchun 130061, China
| | - Deyu Wang
- Bethune Institute of Epigenetic Medicine, The First Hospital of Jilin University, Changchun 130061, China
| | - Rui Zhang
- Bethune Institute of Epigenetic Medicine, The First Hospital of Jilin University, Changchun 130061, China
| | - Mingxin Yu
- Department of Infectious Diseases and Center of Infectious Diseases and Pathogen Biology, Key Laboratory of Organ Regeneration and Transplantation of the Ministry of Education, The First Hospital of Jilin University, Changchun 130061, China
| | - Luoyi Zhao
- Department of Infectious Diseases and Center of Infectious Diseases and Pathogen Biology, Key Laboratory of Organ Regeneration and Transplantation of the Ministry of Education, The First Hospital of Jilin University, Changchun 130061, China
| | - Siwei Zhang
- Department of Pharmacology, College of Basic Medical Sciences, Jilin University, Changchun 130000, China
| | - Fangbin Han
- Bethune Institute of Epigenetic Medicine, The First Hospital of Jilin University, Changchun 130061, China.
| | - Ying Zhao
- Bethune Institute of Epigenetic Medicine, The First Hospital of Jilin University, Changchun 130061, China.
| | - Quan Liu
- Department of Infectious Diseases and Center of Infectious Diseases and Pathogen Biology, Key Laboratory of Organ Regeneration and Transplantation of the Ministry of Education, The First Hospital of Jilin University, Changchun 130061, China.
| |
Collapse
|
|
6
|
Hellen DJ, Fay ME, Lee DH, Klindt-Morgan C, Bennett A, Pachura KJ, Grakoui A, Huppert SS, Dawson PA, Lam WA, Karpen SJ. BiliQML: a supervised machine-learning model to quantify biliary forms from digitized whole slide liver histopathological images. Am J Physiol Gastrointest Liver Physiol 2024; 327:G1-G15. [PMID: 38651949 PMCID: PMC11376979 DOI: 10.1152/ajpgi.00058.2024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/22/2024] [Revised: 04/03/2024] [Accepted: 04/09/2024] [Indexed: 04/25/2024]
Abstract
The progress of research focused on cholangiocytes and the biliary tree during development and following injury is hindered by limited available quantitative methodologies. Current techniques include two-dimensional standard histological cell-counting approaches, which are rapidly performed, error prone, and lack architectural context or three-dimensional analysis of the biliary tree in opacified livers, which introduce technical issues along with minimal quantitation. The present study aims to fill these quantitative gaps with a supervised machine-learning model (BiliQML) able to quantify biliary forms in the liver of anti-keratin 19 antibody-stained whole slide images. Training utilized 5,019 researcher-labeled biliary forms, which following feature selection, and algorithm optimization, generated an F score of 0.87. Application of BiliQML on seven separate cholangiopathy models [genetic (Afp-CRE;Pkd1l1null/Fl, Alb-CRE;Rbp-jkfl/fl, and Albumin-CRE;ROSANICD), surgical (bile duct ligation), toxicological (3,5-diethoxycarbonyl-1,4-dihydrocollidine), and therapeutic (Cyp2c70-/- with ileal bile acid transporter inhibition)] allowed for a means to validate the capabilities and utility of this platform. The results from BiliQML quantification revealed biological and pathological differences across these seven diverse models, indicating a highly sensitive, robust, and scalable methodology for the quantification of distinct biliary forms. BiliQML is the first comprehensive machine-learning platform for biliary form analysis, adding much-needed morphologic context to standard immunofluorescence-based histology, and provides clinical and basic science researchers with a novel tool for the characterization of cholangiopathies.NEW & NOTEWORTHY BiliQML is the first comprehensive machine-learning platform for biliary form analysis in whole slide histopathological images. This platform provides clinical and basic science researchers with a novel tool for the improved quantification and characterization of biliary tract disorders.
Collapse
Affiliation(s)
- Dominick J Hellen
- Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Children's Healthcare of Atlanta and Emory University School of Medicine, Atlanta, Georgia, United States
| | - Meredith E Fay
- The Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, Georgia, United States
- Department of Pediatrics, Division of Pediatric Hematology/Oncology, Aflac Cancer Center and Blood Disorders Service of Children's Healthcare of Atlanta, Emory University School of Medicine, Atlanta, Georgia, United States
| | - David H Lee
- Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Children's Healthcare of Atlanta and Emory University School of Medicine, Atlanta, Georgia, United States
| | - Caroline Klindt-Morgan
- Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Children's Healthcare of Atlanta and Emory University School of Medicine, Atlanta, Georgia, United States
| | - Ashley Bennett
- Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Children's Healthcare of Atlanta and Emory University School of Medicine, Atlanta, Georgia, United States
| | - Kimberly J Pachura
- Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Children's Healthcare of Atlanta and Emory University School of Medicine, Atlanta, Georgia, United States
| | - Arash Grakoui
- Emory National Primate Research Center, Division of Microbiology and Immunology, Emory Vaccine Center, Emory University School of Medicine, Atlanta, Georgia, United States
| | - Stacey S Huppert
- Division of Gastroenterology, Hepatology, and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, United States
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, United States
| | - Paul A Dawson
- Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Children's Healthcare of Atlanta and Emory University School of Medicine, Atlanta, Georgia, United States
| | - Wilbur A Lam
- The Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, Georgia, United States
- Department of Pediatrics, Division of Pediatric Hematology/Oncology, Aflac Cancer Center and Blood Disorders Service of Children's Healthcare of Atlanta, Emory University School of Medicine, Atlanta, Georgia, United States
| | - Saul J Karpen
- Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Children's Healthcare of Atlanta and Emory University School of Medicine, Atlanta, Georgia, United States
| |
Collapse
|
|
7
|
Zhu L, Litts B, Wang Y, Rein JA, Atzrodt CL, Chinnarasu S, An J, Thorson AS, Xu Y, Stafford JM. Ablation of IFNγ in myeloid cells suppresses liver inflammation and fibrogenesis in mice with hepatic small heterodimer partner (SHP) deletion. Mol Metab 2024; 83:101932. [PMID: 38589002 PMCID: PMC11035112 DOI: 10.1016/j.molmet.2024.101932] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/30/2024] [Revised: 03/21/2024] [Accepted: 03/29/2024] [Indexed: 04/10/2024] Open
Abstract
BACKGROUND Metabolic dysfunction-associated steatotic liver disease (MASLD) is a common complication of obesity and, in severe cases, progresses to metabolic dysfunction-associated steatohepatitis (MASH). Small heterodimer partner (SHP) is an orphan member of the nuclear receptor superfamily and regulates metabolism and inflammation in the liver via a variety of pathways. In this study, we investigate the molecular foundation of MASH progression in mice with hepatic SHP deletion and explore possible therapeutic means to reduce MASH. METHODS Hepatic SHP knockout mice (SHPΔhep) and their wild-type littermates (SHPfl/fl) of both sexes were fed a fructose diet for 14 weeks and subjected to an oral glucose tolerance test. Then, plasma lipids were determined, and liver lipid metabolism and inflammation pathways were analyzed with immunoblotting, RNAseq, and qPCR assays. To explore possible therapeutic intersections of SHP and inflammatory pathways, SHPΔhep mice were reconstituted with bone marrow lacking interferon γ (IFNγ-/-) to suppress inflammation. RESULTS Hepatic deletion of SHP in mice fed a fructose diet decreased liver fat and increased proteins for fatty acid oxidation and liver lipid uptake, including UCP1, CPT1α, ACDAM, and SRBI. Despite lower liver fat, hepatic SHP deletion increased liver inflammatory F4/80+ cells and mRNA levels of inflammatory cytokines (IL-12, IL-6, Ccl2, and IFNγ) in both sexes and elevated endoplasmic reticulum stress markers of Cox2 and CHOP in female mice. Liver bulk RNAseq data showed upregulation of genes whose protein products regulate lipid transport, fatty acid oxidation, and inflammation in SHPΔhep mice. The increased inflammation and fibrosis in SHPΔhep mice were corrected with bone marrow-derived IFNγ-/- myeloid cell transplantation. CONCLUSION Hepatic deletion of SHP improves fatty liver but worsens hepatic inflammation possibly by driving excess fatty acid oxidation, which is corrected by deletion of IFNγ specifically in myeloid cells. This suggests that hepatic SHP limits fatty acid oxidation during fructose diet feeding but, in doing so, prevents pro-MASH pathways. The IFNγ-mediated inflammation in myeloid cells appears to be a potential therapeutic target to suppress MASH.
Collapse
Affiliation(s)
- Lin Zhu
- Department of Medicine, Division of Diabetes, Endocrinology and Metabolism, USA
| | - Bridget Litts
- Department of Medicine, Division of Diabetes, Endocrinology and Metabolism, USA
| | - Yu Wang
- Department of Biostatistics, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Jeffrey A Rein
- Department of Medicine, Division of Diabetes, Endocrinology and Metabolism, USA
| | | | | | - Julia An
- Department of Medicine, Division of Diabetes, Endocrinology and Metabolism, USA
| | - Ariel S Thorson
- Department of Molecular Physiology & Biophysics, Vanderbilt University, USA
| | - Yaomin Xu
- Department of Biostatistics, Vanderbilt University Medical Center, Nashville, TN, USA
| | - John M Stafford
- Tennessee Valley Health System, Veterans Affairs, Nashville, TN, USA; Department of Molecular Physiology & Biophysics, Vanderbilt University, USA; Department of Medicine, Division of Diabetes, Endocrinology and Metabolism, USA.
| |
Collapse
|
|
8
|
Jin Y, Wang C, Zhang B, Sun Y, Ji J, Cai Q, Jiang J, Zhang Z, Zhao L, Yu B, Zhang J. Blocking EGR1/TGF-β1 and CD44s/STAT3 Crosstalk Inhibits Peritoneal Metastasis of Gastric Cancer. Int J Biol Sci 2024; 20:1314-1331. [PMID: 38385088 PMCID: PMC10878142 DOI: 10.7150/ijbs.90598] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2023] [Accepted: 01/19/2024] [Indexed: 02/23/2024] Open
Abstract
Peritoneal metastasis (PM) continues to limit the clinical efficacy of gastric cancer (GC). Early growth response 1 (EGR1) plays an important role in tumor cell proliferation, angiogenesis and invasion. However, the role of EGR1 derived from the tumor microenvironment in reshaping the phenotypes of GC cells and its specific molecular mechanisms in increasing the potential for PM are still unclear. In this study, we reported that EGR1 was significantly up-regulated in mesothelial cells from GC peritoneal metastases, leading to enhanced epithelial-mesenchymal transformation (EMT) and stemness phenotypes of GC cells under co-culture conditions. These phenotypes were achieved through the transcription and secretion of TGF-β1 by EGR1 in mesothelial cells, which could regulate the expression and internalization of CD44s. After being internalized into the cytoplasm, CD44s interacted with STAT3 to promote STAT3 phosphorylation and activation, and induced EMT and stemness gene transcription, thus positively regulating the metastasis of GC cells. Moreover, TGF-β1 secretion in the PM microenvironment was significantly increased compared with the matched primary tumor. The blocking effect of SHR-1701 on TGF-β1 was verified by inhibiting peritoneal metastases in xenografts. Collectively, the interplay of EGR1/TGF-β1/CD44s/STAT3 signaling between mesothelial cells and GC cells induces EMT and stemness phenotypes, offering potential as a therapeutic target for PM of GC.
Collapse
Affiliation(s)
- Yangbing Jin
- Department of Oncology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Chao Wang
- Department of Oncology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Benyan Zhang
- Department of Pathology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Ying Sun
- Department of Oncology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Jun Ji
- Department of General Surgery, Shanghai Key Laboratory of Gastric Neoplasms, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Qu Cai
- Department of Oncology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Jinling Jiang
- Department of Oncology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Zhihao Zhang
- Clinical Research and Development, Jiangsu Hengrui Pharmaceuticals Co. Ltd, Shanghai, 201203, China
| | - Liqin Zhao
- Department of Oncology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Beiqin Yu
- Department of General Surgery, Shanghai Key Laboratory of Gastric Neoplasms, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Jun Zhang
- Department of Oncology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
- Department of Oncology, Wuxi Branch of Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, No 197 Zhixian Road, Xinwu District, Wuxi, 214028, China
| |
Collapse
|
|
9
|
Huang Y, Liangpunsakul S, Rudraiah S, Ma J, Keshipeddy SK, Wright D, Costa A, Burgess D, Zhang Y, Huda N, Wang L, Yang Z. HMGB2 is a potential diagnostic marker and therapeutic target for liver fibrosis and cirrhosis. Hepatol Commun 2023; 7:e0299. [PMID: 37930124 PMCID: PMC10629741 DOI: 10.1097/hc9.0000000000000299] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/06/2023] [Accepted: 08/23/2023] [Indexed: 11/07/2023] Open
Abstract
BACKGROUND High mobility group proteins 1 and 2 (HMGB1 and HMGB2) are 80% conserved in amino acid sequence. The function of HMGB1 in inflammation and fibrosis has been extensively characterized. However, an unaddressed central question is the role of HMGB2 on liver fibrosis. In this study, we provided convincing evidence that the HMGB2 expression was significantly upregulated in human liver fibrosis and cirrhosis, as well as in several mouse liver fibrosis models. METHODS The carbon tetrachloride (CCl4) induced liver fibrosis mouse model was used. AAV8-Hmgb2 was utilized to overexpress Hmgb2 in the liver, while Hmgb2-/- mice were used for loss of function experiments. The HMGB2 inhibitor inflachromene and liposome-shHMGB2 (lipo-shHMGB2) were employed for therapeutic intervention. RESULTS The serum HMGB2 levels were also markedly elevated in patients with liver fibrosis and cirrhosis. Deletion of Hmgb2 in Hmgb2-/- mice or inhibition of HMGB2 in mice using a small molecule ICM slowed the progression of CCl4-induced liver fibrosis despite constant HMGB1 expression. In contrast, AAV8-mediated overexpression of Hmgb2 enchanced CCl4-incuded liver fibrosis. Primary hepatic stellate cells (HSCs) isolated from Hmgb2-/- mice showed significantly impaired transdifferentiation and diminished activation of α-SMA, despite a modest induction of HMGB1 protein. RNA-seq analysis revealed the induction of top 45 CCl4-activated genes in multiple signaling pathways including integrin signaling and inflammation. The activation of these genes by CCl4 were abolished in Hmgb2-/- mice or in ICM-treated mice. These included C-X3-C motif chemokine receptor 1 (Cx3cr1) associated with inflammation, cyclin B (Ccnb) associated with cell cycle, DNA topoisomerase 2-alpha (Top2a) associated with intracellular component, and fibrillin (Fbn) and fibromodulin (Fmod) associated with extracellular matrix. CONCLUSION We conclude that HMGB2 is indispensable for stellate cell activation. Therefore, HMGB2 may serve as a potential therapeutic target to prevent HSC activation during chronic liver injury. The blood HMGB2 level may also serve as a potential diagnostic marker to detect early stage of liver fibrosis and cirrhosis in humans.
Collapse
Affiliation(s)
- Yi Huang
- Department of Physiology and Neurobiology, University of Connecticut, Storrs, Connecticut, USA
| | - Suthat Liangpunsakul
- Department of Medicine, Division of Gastroenterology and Hepatology, Indiana University, Indianapolis, Indiana, USA
- Medicine Service, Roudebush Veterans Administration Medical Center, Indianapolis, Indiana, USA
| | - Swetha Rudraiah
- Department of Physiology and Neurobiology, University of Connecticut, Storrs, Connecticut, USA
| | - Jing Ma
- Department of Medicine, Division of Gastroenterology and Hepatology, Indiana University, Indianapolis, Indiana, USA
| | - Santosh K. Keshipeddy
- Department of Pharmaceutical Sciences, School of Pharmacy, University of Connecticut, Storrs, Connecticut, USA
| | - Dennis Wright
- Department of Pharmaceutical Sciences, School of Pharmacy, University of Connecticut, Storrs, Connecticut, USA
| | - Antonio Costa
- Department of Pharmaceutical Sciences, School of Pharmacy, University of Connecticut, Storrs, Connecticut, USA
| | - Diane Burgess
- Department of Pharmaceutical Sciences, School of Pharmacy, University of Connecticut, Storrs, Connecticut, USA
| | - Yuxia Zhang
- Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas, USA
| | - Nazmul Huda
- Department of Medicine, Division of Gastroenterology and Hepatology, Indiana University, Indianapolis, Indiana, USA
| | - Li Wang
- Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, Tucson, Arizona, USA
| | - Zhihong Yang
- Department of Medicine, Division of Gastroenterology and Hepatology, Indiana University, Indianapolis, Indiana, USA
| |
Collapse
|
|
10
|
Kholodenko IV, Kholodenko RV, Yarygin KN. The Crosstalk between Mesenchymal Stromal/Stem Cells and Hepatocytes in Homeostasis and under Stress. Int J Mol Sci 2023; 24:15212. [PMID: 37894893 PMCID: PMC10607347 DOI: 10.3390/ijms242015212] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2023] [Revised: 10/07/2023] [Accepted: 10/10/2023] [Indexed: 10/29/2023] Open
Abstract
Liver diseases, characterized by high morbidity and mortality, represent a substantial medical problem globally. The current therapeutic approaches are mainly aimed at reducing symptoms and slowing down the progression of the diseases. Organ transplantation remains the only effective treatment method in cases of severe liver pathology. In this regard, the development of new effective approaches aimed at stimulating liver regeneration, both by activation of the organ's own resources or by different therapeutic agents that trigger regeneration, does not cease to be relevant. To date, many systematic reviews and meta-analyses have been published confirming the effectiveness of mesenchymal stromal cell (MSC) transplantation in the treatment of liver diseases of various severities and etiologies. However, despite the successful use of MSCs in clinical practice and the promising therapeutic results in animal models of liver diseases, the mechanisms of their protective and regenerative action remain poorly understood. Specifically, data about the molecular agents produced by these cells and mediating their therapeutic action are fragmentary and often contradictory. Since MSCs or MSC-like cells are found in all tissues and organs, it is likely that many key intercellular interactions within the tissue niches are dependent on MSCs. In this context, it is essential to understand the mechanisms underlying communication between MSCs and differentiated parenchymal cells of each particular tissue. This is important both from the perspective of basic science and for the development of therapeutic approaches involving the modulation of the activity of resident MSCs. With regard to the liver, the research is concentrated on the intercommunication between MSCs and hepatocytes under normal conditions and during the development of the pathological process. The goals of this review were to identify the key factors mediating the crosstalk between MSCs and hepatocytes and determine the possible mechanisms of interaction of the two cell types under normal and stressful conditions. The analysis of the hepatocyte-MSC interaction showed that MSCs carry out chaperone-like functions, including the synthesis of the supportive extracellular matrix proteins; prevention of apoptosis, pyroptosis, and ferroptosis; support of regeneration; elimination of lipotoxicity and ER stress; promotion of antioxidant effects; and donation of mitochondria. The underlying mechanisms suggest very close interdependence, including even direct cytoplasm and organelle exchange.
Collapse
Affiliation(s)
- Irina V. Kholodenko
- Laboratory of Cell Biology, Orekhovich Institute of Biomedical Chemistry, 119121 Moscow, Russia
| | - Roman V. Kholodenko
- Laboratory of Molecular Immunology, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, 117997 Moscow, Russia;
| | - Konstantin N. Yarygin
- Laboratory of Cell Biology, Orekhovich Institute of Biomedical Chemistry, 119121 Moscow, Russia
| |
Collapse
|
|
11
|
Zhou LM, Fan JH, Xu MM, Xiong MY, Wang QJ, Chai X, Li XD, Li XG, Ye XL. Epiberberine regulates lipid synthesis through SHP (NR0B2) to improve non-alcoholic steatohepatitis. Biochim Biophys Acta Mol Basis Dis 2023; 1869:166639. [PMID: 36638873 DOI: 10.1016/j.bbadis.2023.166639] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2022] [Revised: 12/22/2022] [Accepted: 01/04/2023] [Indexed: 01/12/2023]
Abstract
Epiberberine (EPI), extracted from Rhizome Coptidis, has been shown to attenuate hyperlipidemia in vivo. Herein we have studied the mechanism by which EPI is active against non-alcoholic steatohepatitis (NASH) using, mice fed on a methionine- and choline-deficient (MCD) diet and HepG2 cells exposed to free fatty acids (FFA). We show that small heterodimer partner (SHP) protein is key in the regulation of lipid synthesis. In HepG2 cells and in the livers of MCD-fed mice, EPI elevated SHP levels, and this was accompanied by a reduction in sterol regulatory element-binding protein-1c (SREBP-1c) and FASN. Therefore, EPI reduced triglyceride (TG) accumulation in steatotic hepatocytes, even in HepG2 cells treated with siRNA-SHP, and also improved microbiota. Thus, EPI suppresses hepatic TG synthesis and ameliorates liver steatosis by upregulating SHP and inhibiting the SREBP1/FASN pathway, and improves gut microbiome.
Collapse
Affiliation(s)
- Li-Ming Zhou
- Engineering Research Center of Coptis Development & Utilization (Ministry of Education), School of Life Sciences, Southwest University, Chongqing 400715, China
| | - Jin-Hua Fan
- Engineering Research Center of Coptis Development & Utilization (Ministry of Education), School of Life Sciences, Southwest University, Chongqing 400715, China
| | - Min-Min Xu
- Engineering Research Center of Coptis Development & Utilization (Ministry of Education), School of Life Sciences, Southwest University, Chongqing 400715, China
| | - Meng-Yuan Xiong
- Engineering Research Center of Coptis Development & Utilization (Ministry of Education), School of Life Sciences, Southwest University, Chongqing 400715, China
| | - Qiao-Jiao Wang
- Engineering Research Center of Coptis Development & Utilization (Ministry of Education), School of Life Sciences, Southwest University, Chongqing 400715, China
| | - Xue Chai
- Engineering Research Center of Coptis Development & Utilization (Ministry of Education), School of Life Sciences, Southwest University, Chongqing 400715, China
| | - Xiao-Duo Li
- Engineering Research Center of Coptis Development & Utilization (Ministry of Education), School of Life Sciences, Southwest University, Chongqing 400715, China
| | - Xue-Gang Li
- School of Pharmaceutical Sciences and Chinese Medicine, Southwest University, Chongqing 400716, China.
| | - Xiao-Li Ye
- Engineering Research Center of Coptis Development & Utilization (Ministry of Education), School of Life Sciences, Southwest University, Chongqing 400715, China.
| |
Collapse
|
|
12
|
Li S, Ye Q, Wei J, Taleb SJ, Wang H, Zhang Y, Kass DJ, Horowitz JC, Zhao J, Zhao Y. Nedd4L suppression in lung fibroblasts facilitates pathogenesis of lung fibrosis. Transl Res 2023; 253:1-7. [PMID: 36257596 PMCID: PMC10167741 DOI: 10.1016/j.trsl.2022.10.002] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/09/2022] [Revised: 10/03/2022] [Accepted: 10/11/2022] [Indexed: 11/06/2022]
Abstract
Ubiquitination-mediated protein degradation is associated with the development of pulmonary fibrosis. We and others have shown that Nedd4L plays anti-inflammatory and anti-fibrotic roles by targeting lysophosphatidic acid receptor 1 (LPAR1), p-Smad2/3, and β-catenin, and other molecules for their degradation in lung epithelial cells and fibroblasts. However, the molecular regulation of Nedd4L expression in lung fibroblasts has not been studied. In this study, we find that Nedd4L levels are significantly suppressed in lung myofibroblasts in IPF patients and in experimental pulmonary fibrosis, and in TGF-β1-treated lung fibroblasts. Nedd4L knockdown promotes TGF-β1-mediated phosphorylation of Smad2/3 and lung myofibroblast differentiation. Mechanistically, Nedd4L targets TGF-β receptor II (TβRII), the first key enzyme of TGF-β1-mediated signaling, for its ubiquitination and degradation. Further, we show that inhibition of transcriptional factor E2F rescues Nedd4L levels and mitigates experimental pulmonary fibrosis. Together, our data reveal insight into mechanisms by which E2F-mediated Nedd4L suppression contributes to the pathogenesis of lung fibrosis. This study provides evidence showing that upregulation of Nedd4L is a potential therapeutic strategy to treat fibrotic disorders including lung fibrosis.
Collapse
Affiliation(s)
- Shuang Li
- Department of Medicine, The University of Pittsburgh, Pittsburgh, PA
| | - Qinmao Ye
- Department of Physiology and Cell Biology, The Ohio State University, Columbus, OH; Dorothy M. Davis Heart & Lung Research Institute, The Ohio State University, Columbus, OH
| | - Jianxin Wei
- Department of Medicine, The University of Pittsburgh, Pittsburgh, PA
| | - Sarah J Taleb
- Department of Physiology and Cell Biology, The Ohio State University, Columbus, OH; Dorothy M. Davis Heart & Lung Research Institute, The Ohio State University, Columbus, OH
| | - Heather Wang
- Department of Physiology and Cell Biology, The Ohio State University, Columbus, OH; Dorothy M. Davis Heart & Lung Research Institute, The Ohio State University, Columbus, OH
| | - Yingze Zhang
- Department of Medicine, The University of Pittsburgh, Pittsburgh, PA
| | - Daniel J Kass
- Department of Medicine, The University of Pittsburgh, Pittsburgh, PA
| | - Jeffrey C Horowitz
- Dorothy M. Davis Heart & Lung Research Institute, The Ohio State University, Columbus, OH; The Department of Internal Medicine, The Ohio State University, Columbus, OH
| | - Jing Zhao
- Department of Physiology and Cell Biology, The Ohio State University, Columbus, OH; Dorothy M. Davis Heart & Lung Research Institute, The Ohio State University, Columbus, OH; The Department of Internal Medicine, The Ohio State University, Columbus, OH
| | - Yutong Zhao
- Department of Physiology and Cell Biology, The Ohio State University, Columbus, OH; Dorothy M. Davis Heart & Lung Research Institute, The Ohio State University, Columbus, OH; The Department of Internal Medicine, The Ohio State University, Columbus, OH.
| |
Collapse
|
|
13
|
Ahi EP, Sinclair-Waters M, Donner I, Primmer CR. A pituitary gene network linking vgll3 to regulators of sexual maturation in male Atlantic salmon. Comp Biochem Physiol A Mol Integr Physiol 2023; 275:111337. [PMID: 36341967 DOI: 10.1016/j.cbpa.2022.111337] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2022] [Revised: 10/20/2022] [Accepted: 10/25/2022] [Indexed: 11/06/2022]
Abstract
Age at maturity is a key life history trait and a significant contributor to life history strategy variation. The maturation process is influenced by genetic and environmental factors, but specific causes of variation in maturation timing remain elusive. In many species, the increase in the regulatory gonadotropin-releasing hormone 1 (GnRH1) marks the onset of puberty. Atlantic salmon, however, lacks the gnrh1 gene, suggesting gnrh3 and/or other regulatory factors are involved in the maturation process. Earlier research in Atlantic salmon has found a strong association between alternative alleles of vgll3 and maturation timing. Recently we reported strong induction of gonadotropin genes (fshb and lhb) in the pituitary of Atlantic salmon homozygous for the early maturation allele (E) of vgll3. The induction of gonadotropins was accompanied by increased expression of their direct upstream regulators, c-jun and sf1 (nr5a1b) but the regulatory connection between vgll3 and these regulators has never been investigated in any organism. In this study, we investigated the potential regulatory connection between vgll3 genotypes and these regulators through a stepwise approach of identifying a gene regulatory network (GRN) containing c-jun and sf1, and transcription factor motif enrichment analysis. We found a GRN containing c-jun with predicted upstream regulators, e2f1, egr1, foxj1 and klf4, to be differentially expressed in the pituitary. Finally, we suggest a vgll3 and Hippo pathway -dependent model for transcriptional regulation of c-jun and sf1 in the pituitary, which may have broader implications across vertebrates.
Collapse
Affiliation(s)
- Ehsan Pashay Ahi
- Organismal and Evolutionary Biology Research Programme, Faculty of Biological and Environmental Sciences, University of Helsinki, Viikinkaari 9, 00014 Helsinki, Finland.
| | - Marion Sinclair-Waters
- Organismal and Evolutionary Biology Research Programme, Faculty of Biological and Environmental Sciences, University of Helsinki, Viikinkaari 9, 00014 Helsinki, Finland; Centre d'Ecologie Fonctionelle et Evolutive, Centre National de la Recherche Scientifique, Montpellier, France. https://twitter.com/Marionswaters
| | - Iikki Donner
- Organismal and Evolutionary Biology Research Programme, Faculty of Biological and Environmental Sciences, University of Helsinki, Viikinkaari 9, 00014 Helsinki, Finland.
| | - Craig R Primmer
- Organismal and Evolutionary Biology Research Programme, Faculty of Biological and Environmental Sciences, University of Helsinki, Viikinkaari 9, 00014 Helsinki, Finland; Institute of Biotechnology, Helsinki Institute of Life Science (HiLIFE), University of Helsinki, Finland.
| |
Collapse
|
|
14
|
Niu Q, Wang T, Wang Z, Wang F, Huang D, Sun H, Liu H. Adipose-derived mesenchymal stem cell-secreted extracellular vesicles alleviate non-alcoholic fatty liver disease via delivering miR-223-3p. Adipocyte 2022; 11:572-587. [PMID: 36093813 PMCID: PMC9481107 DOI: 10.1080/21623945.2022.2098583] [Citation(s) in RCA: 36] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/29/2023] Open
Abstract
Increasing studies have identified the potential of mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) in non-alcoholic fatty liver disease (NAFLD) treatment. Hence, we further focused on the potential of adipose-derived MSC (ADSC)-EVs in NAFLD by delivering miR-223-3p. The uptake of isolated ADSC-EVs by hepatocytes was assessed, and the expression of miR-223-3p in ADSC-EVs and hepatocytes was characterized. It was established that miR-223-3p, enriched in ADSC-EVs, could be delivered by ADSC-EVs into hepatocytes. Using co-culture system and gain-of-function approach, we evaluated the effect of ADSC-EVs carrying miR-223-3p on lipid accumulation and liver fibrosis in pyrrolizidine alkaloids (PA)-induced hepatocytes and a high-fat diet-induced NAFLD mouse model. Bioinformatics websites and dual-luciferase reporter gene assay were performed to determine the interactions between miR-223-3p and E2F1, which was further validated by rescue experiments. ADSC-EVs containing miR-223-3p displayed suppressive effects on lipid accumulation and liver fibrosis through E2F1 inhibition, since E2F1 was demonstrated as a target gene of miR-223-3p. The protective role of ADSC-EVs by delivering miR-223-3p was then confirmed in the mouse model. Collectively, this study elucidated that ADSC-EVs delayed the progression NAFLD through the delivery of anti-fibrotic miR-223-3p and subsequent E2F1 suppression, which may suggest miR-223-3p-loaded ADSC-EVs to be a potential therapeutic approach for NAFLD.
Collapse
Affiliation(s)
- Qinghui Niu
- Department of Liver Center, the Affiliated Hospital of Qingdao University, QingdaoP.R. China
| | - Ting Wang
- Department of Infectious Diseases, the Affiliated Hospital of Qingdao University, QingdaoP.R. China
| | - Zhiqiang Wang
- Department of Infectious Diseases, the Affiliated Hospital of Qingdao University, QingdaoP.R. China
| | - Feng Wang
- Department of Infectious Diseases, the Affiliated Hospital of Qingdao University, QingdaoP.R. China
| | - Deyu Huang
- Department of Infectious Diseases, the Affiliated Hospital of Qingdao University, QingdaoP.R. China
| | - Huali Sun
- Department of Infectious Diseases, the Affiliated Hospital of Qingdao University, QingdaoP.R. China
| | - Hanyun Liu
- Department of Infectious Diseases, the Affiliated Hospital of Qingdao University, QingdaoP.R. China,CONTACT Hanyun Liu Department of Infectious Diseases, the Affiliated Hospital of Qingdao University, No.16, Jiangsu Road, Qingdao266003, Shandong Province, P.R. China
| |
Collapse
|
|
15
|
Huang J, Cao Y, Li X, Yu F, Han X. E2F1 regulates miR-215-5p to aggravate paraquat-induced pulmonary fibrosis via repressing BMPR2 expression. Toxicol Res (Camb) 2022; 11:940-950. [PMID: 36569483 PMCID: PMC9773066 DOI: 10.1093/toxres/tfac071] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2022] [Revised: 09/12/2022] [Accepted: 09/21/2022] [Indexed: 02/01/2023] Open
Abstract
Background Pulmonary fibrosis is considered to be an irreversible lung injury, which can be caused by paraquat (PQ) poisoning. MiRNAs have been demonstrated crucial roles in pulmonary fibrosis caused by numerous approaches including PQ induction. The purpose of this study was to investigate the role and the underlying mechanism of miR-215 in PQ-induced pulmonary fibrosis. Methods The cell and animal models of pulmonary fibrosis were established through PQ intervention. Cell viability was performed to test by MTT assay. Immunofluorescence assay was used to detect COL1A1 expression and its location. The relationships among E2F1, miR-215-5p, and BMPR2 were validated by dual luciferase reporter gene assay, chromatin immunoprecipitation and RNA-binding protein immunoprecipitation. Lung morphology was evaluated by hematoxylin and eosin staining. Results MiR-215-5p was upregulated in PQ-induced pulmonary fibrosis in vitro and in vivo. MiR-215-5p silencing relieved PQ-induced pulmonary fibrosis progression by enhancing cell viability and reducing the expression of fibrosis-related markers (COL1A1, COL3A1, and α-SMA). Mechanistically, miR-215-5p directly targeted BMRP2. BMPR2 knockdown abolished the suppressive effects of miR-215-5p knockdown on PQ-induced pulmonary fibrosis. In addition, E2F1 interacted with miR-215-5p promoter and positively regulated miR-215-5p expression. E2F1 downregulation reduced miR-215-5p level and promoted BMPR2 level via regulating TGF-β/Smad3 pathway, and then suppressed PQ-induced pulmonary fibrosis, whereas these effects were compromised by miR-215-5p sufficiency. Conclusion MiR-215-5p was activated by E2F1 to repress BMPR2 expression and activate TGF-β/Smad3 pathway, which aggravated PQ-induced pulmonary fibrosis progression. Targeting the E2F1/miR-215-5p/BMPR2 axis might be a new approach to alleviate PQ-induced pulmonary fibrosis.
Collapse
Affiliation(s)
- Jie Huang
- Emergency Department, Hunan Provincial People's Hospital/The First Affiliated Hospital of Hunan Normal University, No.61, Jiefang west Road, Furong District, Changsha, Hunan Province 410005, P. R. China
| | - Yan Cao
- Emergency Department, Hunan Provincial People's Hospital/The First Affiliated Hospital of Hunan Normal University, No.61, Jiefang west Road, Furong District, Changsha, Hunan Province 410005, P. R. China
| | - Xiang Li
- Emergency Department, Hunan Provincial People's Hospital/The First Affiliated Hospital of Hunan Normal University, No.61, Jiefang west Road, Furong District, Changsha, Hunan Province 410005, P. R. China
| | - Fang Yu
- Emergency Department, Hunan Provincial People's Hospital/The First Affiliated Hospital of Hunan Normal University, No.61, Jiefang west Road, Furong District, Changsha, Hunan Province 410005, P. R. China
| | - Xiaotong Han
- Emergency Department, Hunan Provincial People's Hospital/The First Affiliated Hospital of Hunan Normal University, No.61, Jiefang west Road, Furong District, Changsha, Hunan Province 410005, P. R. China
| |
Collapse
|
|
16
|
Kimura M, Nishikawa K, Osawa Y, Imamura J, Yamaji K, Harada K, Yatsuhashi H, Murata K, Miura K, Tanaka A, Kanto T, Kohara M, Kamisawa T, Kimura K. Inhibition of CBP/β-catenin signaling ameliorated fibrosis in cholestatic liver disease. Hepatol Commun 2022; 6:2732-2747. [PMID: 35855613 PMCID: PMC9512479 DOI: 10.1002/hep4.2043] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/04/2022] [Revised: 06/02/2022] [Accepted: 06/25/2022] [Indexed: 11/11/2022] Open
Abstract
Chronic cholestatic liver diseases are characterized by injury of the bile ducts and hepatocytes caused by accumulated bile acids (BAs) and inflammation. Wnt/β-catenin signaling is implicated in organ fibrosis; however, its role in cholestatic liver fibrosis remains unclear. Therefore, we explored the effect of a selective cAMP response element-binding protein-binding protein (CBP)/β-catenin inhibitor, PRI-724, on murine cholestatic liver fibrosis. PRI-724 suppressed liver fibrosis induced by multidrug resistance protein 2 knockout (KO), bile duct ligation, or a 3.5-diethoxycarbonyl-1.4-dihydrocollidine (DDC) diet; it also suppressed BA synthesis and macrophage infiltration. The expression of early growth response-1 (Egr-1), which plays a key role in BA synthesis, was increased in the hepatocytes of patients with cholestatic liver disease. PRI-724 inhibited Egr-1 expression induced by cholestasis, and adenoviral shEgr-1-mediated Egr-1 knockdown suppressed BA synthesis and fibrosis in DDC diet-fed mice, suggesting that PRI-724 exerts its effects, at least in part, by suppressing Egr-1 expression in hepatocytes. Hepatocyte-specific CBP KO in mice suppressed BA synthesis, liver injury, and fibrosis, whereas hepatocyte-specific KO of P300, a CBP homolog, exacerbated DDC-induced fibrosis. Intrahepatic Egr-1 expression was also decreased in hepatocyte-specific CBP-KO mice and increased in P300-KO mice, indicating that Egr-1 is located downstream of CBP/β-catenin signaling. Conclusion: PRI-724 inhibits cholestatic liver injury and fibrosis by inhibiting BA synthesis in hepatocytes. These results highlight the therapeutic effect of CBP/β-catenin inhibition in cholestatic liver diseases.
Collapse
Affiliation(s)
- Masamichi Kimura
- Department of HepatologyTokyo Metropolitan Cancer and Infectious Diseases CenterKomagome HospitalTokyoJapan
| | - Koji Nishikawa
- Department of HepatologyTokyo Metropolitan Cancer and Infectious Diseases CenterKomagome HospitalTokyoJapan
| | - Yosuke Osawa
- Department of GastroenterologyInternational University of Health and Welfare HospitalNasushiobaraJapan
| | - Jun Imamura
- Department of HepatologyTokyo Metropolitan Cancer and Infectious Diseases CenterKomagome HospitalTokyoJapan
| | - Kenzaburo Yamaji
- Department of Microbiology and Cell BiologyTokyo Metropolitan Institute of Medical ScienceTokyoJapan
| | - Kenichi Harada
- Department of Human PathologyKanazawa University Graduate School of MedicineKanazawaJapan
| | - Hiroshi Yatsuhashi
- Clinical Research CenterNational Hospital Organization Nagasaki Medical CenterOmuraJapan
| | - Kazumoto Murata
- Division of VirologyDepartment of Infection and ImmunityJichi Medical University School of MedicineTochigiJapan
| | - Kouichi Miura
- Division of GastroenterologyDepartment of MedicineJichi Medical UniversityTochigiJapan
| | - Atsushi Tanaka
- Department of MedicineTeikyo University School of MedicineTokyoJapan
| | - Tatsuya Kanto
- The Research Center for Hepatitis and ImmunologyNational Center for Global Health and MedicineIchikawaJapan
| | - Michinori Kohara
- Department of Microbiology and Cell BiologyTokyo Metropolitan Institute of Medical ScienceTokyoJapan
| | - Terumi Kamisawa
- Department of GastroenterologyTokyo Metropolitan Cancer and Infectious Diseases CenterKomagome HospitalTokyoJapan
| | - Kiminori Kimura
- Department of HepatologyTokyo Metropolitan Cancer and Infectious Diseases CenterKomagome HospitalTokyoJapan
| |
Collapse
|
|
17
|
Zhou B, Luo Y, Ji N, Mao F, Xiang L, Bian H, Zheng MH, Hu C, Li Y, Lu Y. Promotion of nonalcoholic steatohepatitis by RNA N 6-methyladenosine reader IGF2BP2 in mice. LIFE METABOLISM 2022; 1:161-174. [PMID: 39872354 PMCID: PMC11749640 DOI: 10.1093/lifemeta/loac006] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/04/2022] [Revised: 04/20/2022] [Accepted: 06/07/2022] [Indexed: 01/30/2025]
Abstract
Nonalcoholic steatohepatitis (NASH) has emerged as the major cause of end-stage liver diseases. However, an incomplete understanding of its molecular mechanisms severely dampens the development of pharmacotherapies. In the present study, through systematic screening of genome-wide mRNA expression from three mouse models of hepatic inflammation and fibrosis, we identified IGF2BP2, an N6-methyladenosine modification reader, as a key regulator that promotes NASH progression in mice. Adenovirus or adeno-associated virus-mediated overexpression of IGF2BP2 could induce liver steatosis, inflammation, and fibrosis in mice, at least in part, by increasing Tab2 mRNA stability. Besides, hepatic overexpression of IGF2BP2 mimicked gene expression profiles and molecular pathways of human NASH livers. Of potential clinical significance, IGF2BP2 expression is significantly upregulated in the livers of NASH patients. Moreover, knockdown of IGF2BP2 substantially alleviated liver injury, inflammation, and fibrosis in diet-induced NASH mice. Taken together, our findings reveal an important role of IGF2BP2 in NASH, which may provide a new therapeutic target for the treatment of NASH.
Collapse
Affiliation(s)
- Bing Zhou
- Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Clinical Centre for Diabetes, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai, China
- Key Laboratory of Metabolism and Molecular Medicine of the Ministry of Education, Department of Endocrinology and Metabolism of Zhongshan Hospital, Fudan University, Shanghai, China
| | - Yunchen Luo
- Department of Endocrinology and Metabolism, Shanghai General Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Nana Ji
- Key Laboratory of Metabolism and Molecular Medicine of the Ministry of Education, Department of Endocrinology and Metabolism of Zhongshan Hospital, Fudan University, Shanghai, China
- Department of Endocrinology and Metabolism, Qingpu Branch of Zhongshan Hospital, Fudan University, Wenzhou, China
| | - Fei Mao
- Key Laboratory of Metabolism and Molecular Medicine of the Ministry of Education, Department of Endocrinology and Metabolism of Zhongshan Hospital, Fudan University, Shanghai, China
| | - Liping Xiang
- Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Clinical Centre for Diabetes, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai, China
| | - Hua Bian
- Key Laboratory of Metabolism and Molecular Medicine of the Ministry of Education, Department of Endocrinology and Metabolism of Zhongshan Hospital, Fudan University, Shanghai, China
| | - Ming-Hua Zheng
- NAFLD Research Center, Department of Hepatology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
- Key Laboratory of Diagnosis and Treatment for The Development of Chronic Liver Disease in Zhejiang Province, Wenzhou, China
| | - Cheng Hu
- Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Clinical Centre for Diabetes, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai, China
- Department of Endocrinology and Metabolism, Fengxian Central Hospital Affiliated to the Southern Medical University, Shanghai, China
| | - Yao Li
- Department of Laboratory Animal Science, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yan Lu
- Key Laboratory of Metabolism and Molecular Medicine of the Ministry of Education, Department of Endocrinology and Metabolism of Zhongshan Hospital, Fudan University, Shanghai, China
- Institute of Metabolism and Regenerative Medicine, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai, China
| |
Collapse
|
|
18
|
Loss of YB-1 alleviates liver fibrosis by suppressing epithelial-mesenchymal transition in hepatic progenitor cells. Biochim Biophys Acta Mol Basis Dis 2022; 1868:166510. [DOI: 10.1016/j.bbadis.2022.166510] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2022] [Revised: 07/26/2022] [Accepted: 07/27/2022] [Indexed: 11/19/2022]
|
|
19
|
Wei M, Zhang Y, Zhang H, Huang Z, Miao H, Zhang T, Lu B, Ji L. HMGB1 induced endothelial to mesenchymal transition in liver fibrosis: The key regulation of early growth response factor 1. Biochim Biophys Acta Gen Subj 2022; 1866:130202. [PMID: 35820641 DOI: 10.1016/j.bbagen.2022.130202] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2022] [Revised: 06/29/2022] [Accepted: 07/06/2022] [Indexed: 11/25/2022]
Abstract
BACKGROUND Liver fibrosis has been the focus and difficulty of medical research in the world and its concrete pathogenesis remains unclear. This study aims to observe the high-mobility group box 1 (HMGB1)-induced hepatic endothelial to mesenchymal transition (EndoMT) during the development of hepatic fibrosis, and further to explore the crucial involvement of Egr1 in this process. METHODS Carbon tetrachloride (CCl4), diosbulbin B (DB), N-acetyl-p-aminophenol (APAP) and bile duct ligation (BDL) were used to induce liver fibrosis in mice. Serum HMGB1 content, the occurrence of EndoMT and the production of extracellular matrix (ECM) in vitro and in vivo were detected by Western-blot. RESULTS The elevated serum HMGB1 content, the occurrence of EndoMT, the production of ECM and the activation of Egr1 were observed in mice with liver fibrosis induced by CCl4, DB, APAP or BDL. HMGB1 induced EndoMT and ECM production in human hepatic sinusoidal endothelial cells (HHSECs), and then HHSECs lost the ability to inhibit the activation of hepatic stellate cells (HSCs). The hepatic deposition of collagen, the increased serum HMGB1 content and hepatic EndoMT were further aggravated in Egr1 knockout mice. Natural compound silymarin attenuated liver fibrosis in mice induced by CCl4 via increasing Egr1 nuclear accumulation, decreasing serum HMGB1 content and inhibiting hepatic EndoMT. CONCLUSION Egr1 regulated the expression of HMGB1 that induced hepatic EndoMT, which plays an important role in the development of liver fibrosis. GENERAL SIGNIFICANCE This study provides a novel therapeutic strategy for the treatment of liver fibrosis in clinic.
Collapse
Affiliation(s)
- Mengjuan Wei
- The MOE Key Laboratory for Standardization of Chinese Medicines, Shanghai Key Laboratory of Compound Chinese Medicines and The SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Yi Zhang
- The MOE Key Laboratory for Standardization of Chinese Medicines, Shanghai Key Laboratory of Compound Chinese Medicines and The SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Hong Zhang
- The MOE Key Laboratory for Standardization of Chinese Medicines, Shanghai Key Laboratory of Compound Chinese Medicines and The SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Zhenlin Huang
- The MOE Key Laboratory for Standardization of Chinese Medicines, Shanghai Key Laboratory of Compound Chinese Medicines and The SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Hui Miao
- The MOE Key Laboratory for Standardization of Chinese Medicines, Shanghai Key Laboratory of Compound Chinese Medicines and The SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Tianyu Zhang
- The MOE Key Laboratory for Standardization of Chinese Medicines, Shanghai Key Laboratory of Compound Chinese Medicines and The SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Bin Lu
- The MOE Key Laboratory for Standardization of Chinese Medicines, Shanghai Key Laboratory of Compound Chinese Medicines and The SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Lili Ji
- The MOE Key Laboratory for Standardization of Chinese Medicines, Shanghai Key Laboratory of Compound Chinese Medicines and The SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
| |
Collapse
|
|
20
|
Qian T, Fujiwara N, Koneru B, Ono A, Kubota N, Jajoriya AK, Tung MG, Crouchet E, Song WM, Marquez CA, Panda G, Hoshida A, Raman I, Li QZ, Lewis C, Yopp A, Rich NE, Singal AG, Nakagawa S, Goossens N, Higashi T, Koh AP, Bian CB, Hoshida H, Tabrizian P, Gunasekaran G, Florman S, Schwarz ME, Hiotis SP, Nakahara T, Aikata H, Murakami E, Beppu T, Baba H, Warren A, Bhatia S, Kobayashi M, Kumada H, Fobar AJ, Parikh ND, Marrero JA, Rwema SH, Nair V, Patel M, Kim-Schulze S, Corey K, O’Leary JG, Klintmalm GB, Thomas DL, Dibas M, Rodriguez G, Zhang B, Friedman SL, Baumert TF, Fuchs BC, Chayama K, Zhu S, Chung RT, Hoshida Y. Molecular Signature Predictive of Long-Term Liver Fibrosis Progression to Inform Antifibrotic Drug Development. Gastroenterology 2022; 162:1210-1225. [PMID: 34951993 PMCID: PMC8934284 DOI: 10.1053/j.gastro.2021.12.250] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/19/2021] [Revised: 12/14/2021] [Accepted: 12/15/2021] [Indexed: 01/02/2023]
Abstract
BACKGROUND & AIMS There is a major unmet need to assess the prognostic impact of antifibrotics in clinical trials because of the slow rate of liver fibrosis progression. We aimed to develop a surrogate biomarker to predict future fibrosis progression. METHODS A fibrosis progression signature (FPS) was defined to predict fibrosis progression within 5 years in patients with hepatitis C virus and nonalcoholic fatty liver disease (NAFLD) with no to minimal fibrosis at baseline (n = 421) and was validated in an independent NAFLD cohort (n = 78). The FPS was used to assess response to 13 candidate antifibrotics in organotypic ex vivo cultures of clinical fibrotic liver tissues (n = 78) and cenicriviroc in patients with nonalcoholic steatohepatitis enrolled in a clinical trial (n = 19, NCT02217475). A serum protein-based surrogate FPS was developed and tested in a cohort of compensated cirrhosis patients (n = 122). RESULTS A 20-gene FPS was defined and validated in an independent NAFLD cohort (adjusted odds ratio, 10.93; area under the receiver operating characteristic curve, 0.86). Among computationally inferred fibrosis-driving FPS genes, BCL2 was confirmed as a potential pharmacologic target using clinical liver tissues. Systematic ex vivo evaluation of 13 candidate antifibrotics identified rational combination therapies based on epigallocatechin gallate, which were validated for enhanced antifibrotic effect in ex vivo culture of clinical liver tissues. In patients with nonalcoholic steatohepatitis treated with cenicriviroc, FPS modulation was associated with 1-year fibrosis improvement accompanied by suppression of the E2F pathway. Induction of the PPARα pathway was absent in patients without fibrosis improvement, suggesting a benefit of combining PPARα agonism to improve the antifibrotic efficacy of cenicriviroc. A 7-protein serum protein-based surrogate FPS was associated with the development of decompensation in cirrhosis patients. CONCLUSION The FPS predicts long-term fibrosis progression in an etiology-agnostic manner, which can inform antifibrotic drug development.
Collapse
Affiliation(s)
- Tongqi Qian
- Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, U.S
| | - Naoto Fujiwara
- Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, U.S.,Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Bhuvaneswari Koneru
- Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, U.S
| | - Atsushi Ono
- Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, U.S.,Department of Gastroenterology and Metabolism, Graduate School of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Naoto Kubota
- Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, U.S
| | - Arun K Jajoriya
- Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, U.S
| | - Matthew G Tung
- Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, U.S
| | - Emilie Crouchet
- Institut de Recherche sur les Maladies Virales et Hépatiques, Inserm U1110, University of Strasbourg, Strasbourg, France
| | - Won-Min Song
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, U.S
| | - Cesia Ammi Marquez
- Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, U.S
| | - Gayatri Panda
- Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, U.S
| | - Ayaka Hoshida
- Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, U.S
| | - Indu Raman
- Microarray Core Facility, Department of Immunology, BioCenter, University of Texas Southwestern Medical Center, Dallas, U.S
| | - Quan-Zhen Li
- Microarray Core Facility, Department of Immunology, BioCenter, University of Texas Southwestern Medical Center, Dallas, U.S
| | - Cheryl Lewis
- Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, U.S
| | - Adam Yopp
- Department of Surgery, University of Texas Southwestern Medical Center, Dallas, U.S
| | - Nicole E Rich
- Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, U.S
| | - Amit G Singal
- Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, U.S
| | - Shigeki Nakagawa
- Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
| | - Nicolas Goossens
- Division of Gastroenterology and Hepatology, Geneva University Hospital, Switzerland
| | - Takaaki Higashi
- Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
| | - Anna P Koh
- Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, U.S
| | - C Billie Bian
- Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, U.S
| | - Hiroki Hoshida
- Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, U.S
| | - Parissa Tabrizian
- Department of Surgery, Icahn School of Medicine at Mount Sinai, New York, U.S
| | - Ganesh Gunasekaran
- Department of Surgery, Icahn School of Medicine at Mount Sinai, New York, U.S
| | - Sander Florman
- Department of Surgery, Icahn School of Medicine at Mount Sinai, New York, U.S
| | - Myron E Schwarz
- Department of Surgery, Icahn School of Medicine at Mount Sinai, New York, U.S
| | - Spiros P Hiotis
- Department of Surgery, Icahn School of Medicine at Mount Sinai, New York, U.S
| | - Takashi Nakahara
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Hiroshi Aikata
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Eisuke Murakami
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Toru Beppu
- Department of Surgery, University of Texas Southwestern Medical Center, Dallas, U.S
| | - Hideo Baba
- Department of Surgery, University of Texas Southwestern Medical Center, Dallas, U.S
| | | | | | | | | | - Austin J Fobar
- Division of Gastroenterology and Hepatology, University of Michigan, Ann Arbor, U.S
| | - Neehar D Parikh
- Division of Gastroenterology and Hepatology, University of Michigan, Ann Arbor, U.S
| | - Jorge A Marrero
- Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, U.S.,Division of Gastroenterology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, U.S
| | | | - Venugopalan Nair
- Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, U.S
| | - Manishkumar Patel
- Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, U.S
| | | | - Kathleen Corey
- Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, U.S
| | | | | | - David L Thomas
- Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, U.S
| | | | | | - Bin Zhang
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, U.S
| | - Scott L Friedman
- Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, U.S
| | - Thomas F Baumert
- Institut de Recherche sur les Maladies Virales et Hépatiques, Inserm U1110, University of Strasbourg, Strasbourg, France.,IHU, Pole hépato-digestif, Strasbourg University Hospitals, Strasbourg, France
| | - Bryan C Fuchs
- Department of Surgery, Massachusetts General Hospital, Boston, U.S., Ferring Pharmaceuticals, San Diego, U.S
| | - Kazuaki Chayama
- Collaborative Research Laboratory of Medical Innovation, Research Center for Hepatology and Gastroenterology, Hiroshima University, Hiroshima, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan
| | - Shijia Zhu
- Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas.
| | - Raymond T Chung
- Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
| | - Yujin Hoshida
- Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas.
| |
Collapse
|
|
21
|
Song Y, Tran M, Wang L, Shin DJ, Wu J. MiR-200c-3p targets SESN1 and represses the IL-6/AKT loop to prevent cholangiocyte activation and cholestatic liver fibrosis. J Transl Med 2022; 102:485-493. [PMID: 34880414 PMCID: PMC9042705 DOI: 10.1038/s41374-021-00710-6] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2021] [Revised: 11/18/2021] [Accepted: 11/19/2021] [Indexed: 01/06/2023] Open
Abstract
Cholestasis causes ductular reaction in the liver where the reactive cholangiocytes not only proliferate but also gain a neuroendocrine-like phenotype, leading to inflammatory cell infiltration and extracellular matrix deposition and contributing to the development and progression of cholestatic liver fibrosis. This study aims to elucidate the role of miR-200c in cholestasis-induced biliary liver fibrosis and cholangiocyte activation. We found that miR-200c was extremely abundant in cholangiocytes but was reduced by cholestasis in a bile duct ligation (BDL) mouse model; miR-200c was also decreased by bile acids in vitro. Phenotypically, loss of miR-200c exacerbated cholestatic liver injury, including periductular fibrosis, intrahepatic inflammation, and biliary hyperplasia in both the BDL model and the 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) model. We identified sestrin 1 (SESN1) as a target of miR-200c. Sesn1-/--BDL mice showed mitigation of cholestatic liver injury. On a molecular level, the pro-proliferative IL-6/AKT feedback loop was activated in Mir200c-/- livers but was inhibited in Sesn1-/- livers upon cholestasis in mice. Furthermore, rescuing expression of miR-200c by the adeno-associated virus serotype 8 ameliorated BDL-induced liver injury in Mir200c-/- mice. Taken together, this study demonstrates that miR-200c restrains the proliferative and neuroendocrine-like activation of cholangiocytes by targeting SESN1 and inhibiting the IL-6/AKT feedback loop to protect against cholestatic liver fibrosis. Our findings provide mechanistic insights regarding biliary liver fibrosis, which may help to reveal novel therapeutic targets for the treatment of cholestatic liver injury and liver fibrosis.
Collapse
Affiliation(s)
- Yongfeng Song
- grid.63054.340000 0001 0860 4915Department of Physiology and Neurobiology, University of Connecticut, Storrs, CT USA ,grid.460018.b0000 0004 1769 9639Department of Endocrinology and Metabolism, Shandong Provincial Hospital affiliated to Shandong First Medical University, Shandong Institute of Endocrinology & Metabolism, Shandong, China
| | - Melanie Tran
- grid.63054.340000 0001 0860 4915Department of Physiology and Neurobiology, University of Connecticut, Storrs, CT USA
| | - Li Wang
- Independent Researcher, Tucson, AZ USA
| | - Dong-Ju Shin
- grid.63054.340000 0001 0860 4915Department of Physiology and Neurobiology, University of Connecticut, Storrs, CT USA
| | - Jianguo Wu
- Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA. .,Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH, USA.
| |
Collapse
|
|
22
|
Lee YH, Jang HJ, Kim S, Choi SS, Khim KW, Eom HJ, Hyun J, Shin KJ, Chae YC, Kim H, Park J, Park NH, Woo CY, Hong CH, Koh EH, Nam D, Choi JH. Hepatic MIR20B promotes nonalcoholic fatty liver disease by suppressing PPARA. eLife 2021; 10:70472. [PMID: 34964438 PMCID: PMC8758141 DOI: 10.7554/elife.70472] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2021] [Accepted: 12/24/2021] [Indexed: 11/13/2022] Open
Abstract
Background Non-alcoholic fatty liver disease (NAFLD) is characterized by excessive lipid accumulation and imbalances in lipid metabolism in the liver. Although nuclear receptors (NRs) play a crucial role in hepatic lipid metabolism, the underlying mechanisms of NR regulation in NAFLD remain largely unclear. Methods Using network analysis and RNA-seq to determine the correlation between NRs and microRNA in human NAFLD patients, we revealed that MIR20B specifically targets PPARA. MIR20B mimic and anti-MIR20B were administered to human HepG2 and Huh-7 cells and mouse primary hepatocytes as well as high fat diet (HFD)- or methionine-deficient diet (MCD)-fed mice to verify the specific function of MIR20B in NAFLD. We tested the inhibition of the therapeutic effect of a PPARα agonist, fenofibrate, by Mir20b and the synergic effect of combination of fenofibrate with anti-Mir20b in NAFLD mouse model. Results We revealed that MIR20B specifically targets PPARA through miRNA regulatory network analysis of nuclear receptor genes in NAFLD. The expression of MIR20B was upregulated in free fatty acid (FA)-treated hepatocytes and the livers of both obesity-induced mice and NAFLD patients. Overexpression of MIR20B significantly increased hepatic lipid accumulation and triglyceride levels. Furthermore, MIR20B significantly reduced FA oxidation and mitochondrial biogenesis by targeting PPARA. In Mir20b-introduced mice, the effect of fenofibrate to ameliorate hepatic steatosis was significantly suppressed. Finally, inhibition of Mir20b significantly increased FA oxidation and uptake, resulting in improved insulin sensitivity and a decrease in NAFLD progression. Moreover, combination of fenofibrate and anti-Mir20b exhibited the synergic effect on improvement of NAFLD in MCD-fed mice. Conclusions Taken together, our results demonstrate that the novel MIR20B targets PPARA, plays a significant role in hepatic lipid metabolism, and present an opportunity for the development of novel therapeutics for NAFLD. Funding This research was funded by Korea Mouse Phenotyping Project (2016M3A9D5A01952411), the National Research Foundation of Korea (NRF) grant funded by the Korea government (2020R1F1A1061267, 2018R1A5A1024340, NRF-2021R1I1A2041463, 2020R1I1A1A01074940), and the Future-leading Project Research Fund (1.210034.01) of UNIST.
Collapse
Affiliation(s)
- Yo Han Lee
- Department of Biological Sciences, Ulsan National Institute of Science and Technology, Ulsan, Republic of Korea
| | - Hyun-Jun Jang
- Department of Biological Sciences, Ulsan National Institute of Science and Technology, Ulsan, Republic of Korea
| | - Sounkou Kim
- Department of Biological Sciences, Ulsan National Institute of Science and Technology, Ulsan, Republic of Korea
| | - Sun Sil Choi
- Department of Biological Sciences, Ulsan National Institute of Science and Technology, Ulsan, Republic of Korea
| | - Keon Woo Khim
- Department of Biological Sciences, Ulsan National Institute of Science and Technology, Ulsan, Republic of Korea
| | - Hye-Jin Eom
- Department of Biological Sciences, Ulsan National Institute of Science and Technology, Ulsan, Republic of Korea
| | - Jimin Hyun
- Department of Biological Sciences, Ulsan National Institute of Science and Technology, Ulsan, Republic of Korea
| | - Kyeong Jin Shin
- Department of Biological Sciences, Ulsan National Institute of Science and Technology, Ulsan, Republic of Korea
| | - Young Chan Chae
- Department of Biological Sciences, Ulsan National Institute of Science and Technology, Ulsan, Republic of Korea
| | - Hongtae Kim
- Department of Biological Sciences, Ulsan National Institute of Science and Technology, Ulsan, Republic of Korea
| | - Jiyoung Park
- Department of Biological Sciences, Ulsan National Institute of Science and Technology, Ulsan, Republic of Korea
| | - Neung Hwa Park
- Department of Internal Medicine, Ulsan University Hospital, Ulsan, Republic of Korea
| | - Chang-Yun Woo
- Department of Internal Medicine, Asan Medical Center, Seoul, Republic of Korea
| | - Chung Hwan Hong
- Department of Medical Science, Asan Medical Center, Seoul, Republic of Korea
| | - Eun Hee Koh
- Department of Internal Medicine, Asan Medical Center, Seoul, Republic of Korea
| | - Dougu Nam
- Department of Biological Sciences, Ulsan National Institute of Science and Technology, Ulsan, Republic of Korea
| | - Jang Hyun Choi
- Department of Biological Sciences, Ulsan National Institute of Science and Technology, Ulsan, Republic of Korea
| |
Collapse
|
|
23
|
Liao R, Xie B, Cui J, Qi Z, Xue S, Wang Y. E2F transcription factor 1 (E2F1) promotes the transforming growth factor TGF-β1 induced human cardiac fibroblasts differentiation through promoting the transcription of CCNE2 gene. Bioengineered 2021; 12:6869-6877. [PMID: 34521301 PMCID: PMC8806588 DOI: 10.1080/21655979.2021.1972194] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022] Open
Abstract
The differentiation of cardiac fibroblast to myofibroblast is the key process of cardiac fibrosis. In the study, we aimed to determine the function of E2F Transcription Factor 1 (E2F1) in human cardiac fibroblasts (HCFs) differentiation, search for its downstream genes and elucidate the function of them in HCFs differentiation. As a result, we found that E2F1 was up-regulated in TGF-β1-induced HCFs differentiation. Silencing the expression of E2F1 by siRNA in HCFs, we found that the expression of differentiation-related genes (Collagen-1, α-Smooth muscle actin, and Fibronectin-1) was significantly suppressed, combining with proliferation and migration assay, we determined that HCFs differentiation was decreased. Luciferase report assay and immunoprecipitation proved that the oncogene CCNE2 was a direct target gene of E2F1, overexpression of CCNE2 was found in differentiated HCFs, silencing the expression of CCNE2 by siRNA decreased HCFs differentiation. Our research suggested that E2F1 and its downstream target gene CCNE2 play a vital role in TGF-β1-induced HCFs differentiation, thus E2F1 and CCNE2 may be a potential therapeutic target for cardiac fibrosis.
Collapse
Affiliation(s)
- Rongheng Liao
- Department of Cardiovascular Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Bo Xie
- Department of Cardiovascular Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Jun Cui
- Department of Cardiovascular Surgery, Xijing Hospital, The Fourth Military Medical University, Xi'an, China
| | - Zhen Qi
- Department of Cardiovascular Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Song Xue
- Department of Cardiovascular Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Yongyi Wang
- Department of Cardiovascular Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| |
Collapse
|
|
24
|
Liao R, Qi Z, Tang R, Wang R, Wang Y. Methyl Ferulic Acid Attenuates Human Cardiac Fibroblasts Differentiation and Myocardial Fibrosis by Suppressing pRB-E2F1/CCNE2 and RhoA/ROCK2 Pathway. Front Pharmacol 2021; 12:714390. [PMID: 34483923 PMCID: PMC8416034 DOI: 10.3389/fphar.2021.714390] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2021] [Accepted: 07/12/2021] [Indexed: 01/12/2023] Open
Abstract
Background: Myocardial fibrosis is a key pathological process after myocardial infarction, which leads to poor outcomes in patients at the end stage. Effective treatments for improving prognosis of myocardial fibrosis are needed to be further developed. Methyl ferulic acid (MFA), a biologically active monomer extracted and purified from the Chinese herbal medicine, is reported as an attenuator in many diseases. In this study, we aim to reveal the role it plays in myocardial fibrosis after myocardial infarction and its possible mechanism. Results: Firstly, we found that MFA attenuated the expression of fibrosis-related proteins and the ability of migration and proliferation in TGF-β1-induced human cardiac fibroblasts (HCFs). Then, myocardial fibrosis after myocardial infarction models on mouse was built to reveal the in vivo affection of MFA. After 28 days of treatments, fibrosis areas, cardiac function, and expression of fibrosis-related proteins were all improved in the MFA-treated group than the myocardial infarction group. Finally, to elucidate the mechanism of phenomenon we observed, we found that MFA attenuated HCF differentiation after myocardial infarction by suppressing the migration and proliferation in HCFs, which was by suppressing the pRB-E2F1/CCNE2 and the RhoA/ROCK2 pathway. Conclusion: Our findings showed that MFA attenuated the expression of fibrosis-related proteins, and the ability of migration and proliferation in HCFs improved the cardiac function of myocardial infarction mice; meanwhile, the mechanism of that was by suppressing the pRB-E2F1/CCNE2 and the RhoA/ROCK2 pathway.
Collapse
Affiliation(s)
- Rongheng Liao
- Department of Cardiovascular Surgery, School of Medicine, Renji Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Zhen Qi
- Department of Cardiovascular Surgery, School of Medicine, Renji Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Ri Tang
- Department of Critical Care Medicine, School of Medicine, Renji Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Renrong Wang
- Department of Cardiology, Wuxi No. 2 Hospital, Nanjing Medical University, Wuxi, China
| | - Yongyi Wang
- Department of Cardiovascular Surgery, School of Medicine, Renji Hospital, Shanghai Jiao Tong University, Shanghai, China
| |
Collapse
|
|
25
|
Yang Z, Smalling RV, Huang Y, Jiang Y, Kusumanchi P, Bogaert W, Wang L, Delker DA, Skill NJ, Han S, Zhang T, Ma J, Huda N, Liangpunsakul S. The role of SHP/REV-ERBα/CYP4A axis in the pathogenesis of alcohol-associated liver disease. JCI Insight 2021; 6:e140687. [PMID: 34423788 PMCID: PMC8410014 DOI: 10.1172/jci.insight.140687] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2020] [Accepted: 07/14/2021] [Indexed: 12/20/2022] Open
Abstract
Alcohol-associated liver disease (ALD) represents a spectrum of histopathological changes, including alcoholic steatosis, steatohepatitis, and cirrhosis. One of the early responses to excessive alcohol consumption is lipid accumulation in the hepatocytes. Lipid ω-hydroxylation of medium- and long-chain fatty acid metabolized by the cytochrome P450 4A (CYP4A) family is an alternative pathway for fatty acid metabolism. The molecular mechanisms of CYP4A in ALD pathogenesis have not been elucidated. In this study, WT and Shp−/− mice were fed with a modified ethanol-binge, National Institute on Alcohol Abuse and Alcoholism model (10 days of ethanol feeding plus single binge). Liver tissues were collected every 6 hours for 24 hours and analyzed using RNA-Seq. The effects of REV-ERBα agonist (SR9009, 100 mg/kg/d) or CYP4A antagonist (HET0016, 5 mg/kg/d) in ethanol-fed mice were also evaluated. We found that hepatic Cyp4a10 and Cyp4a14 expression were significantly upregulated in WT mice, but not in Shp−/− mice, fed with ethanol. ChIP quantitative PCR and promoter assay revealed that REV-ERBα is the transcriptional repressor of Cyp4a10 and Cyp4a14. Rev-Erbα−/− hepatocytes had a marked induction of both Cyp4a genes and lipid accumulation. REV-ERBα agonist SR9009 or CYP4A antagonist HET0016 attenuated Cyp4a induction by ethanol and prevented alcohol-induced steatosis. Here, we have identified a role for the SHP/REV-ERBα/CYP4A axis in the pathogenesis of ALD. Our data also suggest REV-ERBα or CYP4A as the potential therapeutic targets for ALD.
Collapse
Affiliation(s)
- Zhihong Yang
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Rana V Smalling
- Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Yi Huang
- Department of Physiology and Neurobiology, University of Connecticut, Storrs, Connecticut, USA
| | - Yanchao Jiang
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Praveen Kusumanchi
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Will Bogaert
- Department of Physiology and Neurobiology, University of Connecticut, Storrs, Connecticut, USA
| | - Li Wang
- Department of Internal Medicine, Section of Digestive Diseases, Yale University, New Haven, Connecticut, USA
| | - Don A Delker
- Divisions of Gastroenterology, University of Utah, Salt Lake City, Utah, USA
| | - Nicholas J Skill
- Department of Surgery, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Sen Han
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Ting Zhang
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Jing Ma
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Nazmul Huda
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Suthat Liangpunsakul
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA.,Roudebush Veterans Administration Medical Center, Indianapolis, Indiana, USA.,Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana, USA
| |
Collapse
|
|
26
|
Li J, Zhu X, Zhang M, Zhang Y, Ye S, Leng Y, Yang T, Kong L, Zhang H. Limb expression 1-like (LIX1L) protein promotes cholestatic liver injury by regulating bile acid metabolism. J Hepatol 2021; 75:400-413. [PMID: 33746084 DOI: 10.1016/j.jhep.2021.02.035] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/21/2020] [Revised: 01/28/2021] [Accepted: 02/18/2021] [Indexed: 02/08/2023]
Abstract
BACKGROUND & AIMS Cholestatic liver diseases comprise a variety of disorders of bile formation and/or flow which generally result in progressive hepatobiliary injury. Regulation of bile acid (BA) synthesis and homeostasis is a promising strategy for the treatment of cholestatic liver disease. Limb expression 1-like protein (LIX1L) plays an important role in post-transcriptional gene regulation, yet its role in cholestatic liver injury remains unclear. METHODS LIX1L expression was studied in patients with primary sclerosing cholangitis (PSC) or primary biliary cholangitis (PBC), and 3 murine models of cholestasis (bile duct ligation [BDL], Mdr2 knockout [Mdr2-/-], and cholic acid [CA] feeding). Lix1l knockout mice were employed to investigate the function of LIX1L in cholestatic liver diseases. Chromatin immunoprecipitation assays were performed to determine whether Egr-1 bound to the Lix1l promoter. MiRNA expression profiling was analyzed by microarray. An adeno-associated virus (AAV)-mediated hepatic delivery system was used to identify the function of miR-191-3p in vivo. RESULTS LIX1L expression was increased in the livers of patients with PSC and PBC, and in the 3 murine models, as well as in BA-stimulated primary mouse hepatocytes. BA-induced Lix1l upregulation was dependent on Egr-1, which served as a transcriptional activator. LIX1L deficiency attenuated cholestatic liver injury in BDL and Mdr2-/- mice. MiR-191-3p was the most reduced miRNA in livers of WT-BDL mice, while it was restored in Lix1l-/--BDL mice. MiR-191-3p targets and downregulates Lrh-1, thereby inhibiting Cyp7a1 and Cyp8b1 expression. AAV-mediated hepatic delivery of miR-191-3p significantly attenuated cholestatic liver injury in Mdr2-/- mice. CONCLUSIONS LIX1L deficiency alleviates cholestatic liver injury by inhibiting BA synthesis. LIX1L functions as a nexus linking BA/Egr-1 and miR-191-3p/LRH-1 signaling. LIX1L and miR-191-3p may be promising targets for the treatment of BA-associated hepatobiliary diseases. LAY SUMMARY Bile acid homeostasis can be impaired in cholestatic liver diseases. Our study identified a novel mechanism of positive feedback regulation in cholestasis. LIX1L and miR-191-3p represent potential therapeutic targets for cholestatic liver diseases.
Collapse
Affiliation(s)
- Jie Li
- Jiangsu Key Laboratory of Bioactive Natural Product Research and State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 210009, China
| | - Xiaoyun Zhu
- Jiangsu Key Laboratory of Bioactive Natural Product Research and State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 210009, China
| | - Meihui Zhang
- Jiangsu Key Laboratory of Bioactive Natural Product Research and State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 210009, China
| | - Yanqiu Zhang
- Jiangsu Key Laboratory of Bioactive Natural Product Research and State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 210009, China
| | - Shengtao Ye
- Jiangsu Key Laboratory of Bioactive Natural Product Research and State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 210009, China
| | - Yingrong Leng
- Jiangsu Key Laboratory of Bioactive Natural Product Research and State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 210009, China
| | - Ting Yang
- Jiangsu Key Laboratory of Bioactive Natural Product Research and State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 210009, China
| | - Lingyi Kong
- Jiangsu Key Laboratory of Bioactive Natural Product Research and State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 210009, China.
| | - Hao Zhang
- Jiangsu Key Laboratory of Bioactive Natural Product Research and State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 210009, China.
| |
Collapse
|
|
27
|
Liu S, Chen X, Zhang S, Wang X, Du X, Chen J, Zhou G. miR‑106b‑5p targeting SIX1 inhibits TGF‑β1‑induced pulmonary fibrosis and epithelial‑mesenchymal transition in asthma through regulation of E2F1. Int J Mol Med 2021; 47:24. [PMID: 33495833 PMCID: PMC7846424 DOI: 10.3892/ijmm.2021.4857] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2020] [Accepted: 12/21/2020] [Indexed: 02/06/2023] Open
Abstract
Asthma is an inflammatory disease of the airways, characterized by lung eosinophilia, mucus hypersecretion by goblet cells and airway hyper-responsiveness to inhaled allergens. The present study aimed to identify the function of microRNA (miR/miRNA)-106b-5p in TGF-β1-induced pulmonary fibrosis and epithelial-mesenchymal transition (EMT) via targeting sine oculis homeobox homolog 1 (SIX1) through regulation of E2F transcription factor 1 (E2F1) in asthma. Asthmatic mouse models were induced with ovalbumin. miRNA expression was evaluated using reverse transcription-quantitative PCR. Transfection experiments using bronchial epithelial cells were performed to determine the target genes. A luciferase reporter assay system was applied to identify the target gene of miR-106b-5p. The present study revealed downregulated miR-106b-5p expression and upregulated SIX1 expression in asthmatic mice and TGF-β1-induced BEAS-2B cells. Moreover, miR-106b-5p overexpression inhibited TGF-β1-induced fibrosis and EMT in BEAS-2B cells, while miR-106b-5p-knockdown produced the opposite effects. Subsequently, miR-106b-5p was found to regulate SIX1 through indirect regulation of E2F1. Additionally, E2F1- and SIX1-knockdown blocked TGF-β1-induced fibrosis and EMT in BEAS-2B cells. In addition, miR-106b-5p negatively regulated SIX1 via E2F1 in BEAS-2B cells. The present study demonstrated that the miR-106b-5p/E2F1/SIX1 signaling pathway may provide potential therapeutic targets for asthma.
Collapse
Affiliation(s)
- Shuang Liu
- Department of Pediatrics, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, P.R. China
| | - Xi Chen
- Department of Pediatrics, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, P.R. China
| | - Siqing Zhang
- Department of Respiratory Medicine, Children's Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, P.R. China
| | - Xinyu Wang
- Department of Pediatrics, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, P.R. China
| | - Xiaoliu Du
- Department of Pathology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, P.R. China
| | - Jiahe Chen
- Department of Pediatrics, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, P.R. China
| | - Guoping Zhou
- Department of Pediatrics, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, P.R. China
| |
Collapse
|
|
28
|
Rajavel A, Schmitt AO, Gültas M. Computational Identification of Master Regulators Influencing Trypanotolerance in Cattle. Int J Mol Sci 2021; 22:ijms22020562. [PMID: 33429951 PMCID: PMC7827104 DOI: 10.3390/ijms22020562] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2020] [Revised: 12/31/2020] [Accepted: 01/05/2021] [Indexed: 12/15/2022] Open
Abstract
African Animal Trypanosomiasis (AAT) is transmitted by the tsetse fly which carries pathogenic trypanosomes in its saliva, thus causing debilitating infection to livestock health. As the disease advances, a multistage progression process is observed based on the progressive clinical signs displayed in the host’s body. Investigation of genes expressed with regular monotonic patterns (known as Monotonically Expressed Genes (MEGs)) and of their master regulators can provide important clue for the understanding of the molecular mechanisms underlying the AAT disease. For this purpose, we analysed MEGs for three tissues (liver, spleen and lymph node) of two cattle breeds, namely trypanosusceptible Boran and trypanotolerant N’Dama. Our analysis revealed cattle breed-specific master regulators which are highly related to distinguish the genetic programs in both cattle breeds. Especially the master regulators MYC and DBP found in this study, seem to influence the immune responses strongly, thereby susceptibility and trypanotolerance of Boran and N’Dama respectively. Furthermore, our pathway analysis also bolsters the crucial roles of these master regulators. Taken together, our findings provide novel insights into breed-specific master regulators which orchestrate the regulatory cascades influencing the level of trypanotolerance in cattle breeds and thus could be promising drug targets for future therapeutic interventions.
Collapse
Affiliation(s)
- Abirami Rajavel
- Breeding Informatics Group, Department of Animal Sciences, Georg-August University, Margarethe von Wrangell-Weg 7, 37075 Göttingen, Germany; (A.R.); (A.O.S.)
| | - Armin Otto Schmitt
- Breeding Informatics Group, Department of Animal Sciences, Georg-August University, Margarethe von Wrangell-Weg 7, 37075 Göttingen, Germany; (A.R.); (A.O.S.)
- Center for Integrated Breeding Research (CiBreed), Albrecht-Thaer-Weg 3, Georg-August University, 37075 Göttingen, Germany
| | - Mehmet Gültas
- Breeding Informatics Group, Department of Animal Sciences, Georg-August University, Margarethe von Wrangell-Weg 7, 37075 Göttingen, Germany; (A.R.); (A.O.S.)
- Center for Integrated Breeding Research (CiBreed), Albrecht-Thaer-Weg 3, Georg-August University, 37075 Göttingen, Germany
- Correspondence:
| |
Collapse
|
|
29
|
Zhang Y, Li Y, Mu T, Tong N, Cheng P. Hepatic stellate cells specific liposomes with the Toll-like receptor 4 shRNA attenuates liver fibrosis. J Cell Mol Med 2021; 25:1299-1313. [PMID: 33336563 PMCID: PMC7812270 DOI: 10.1111/jcmm.16209] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2020] [Revised: 11/04/2020] [Accepted: 12/04/2020] [Indexed: 02/05/2023] Open
Abstract
The hepatic stellate cells (HSCs) play a significant role in the onset of liver fibrosis, which can be treated by the inhibition and reversal of HSC activation. The RNA interference-mediated TLR4 gene silencing might be a potential therapeutic approach for liver fibrosis. The crucial challenge in this method is the absence of an efficient delivery system for the RNAi introduction in the target cells. HSCs have an enhanced capacity of vitamin A intake as they contain retinoic acid receptors (RARs). In the current study, we developed cationic liposomes modified with vitamin A to improve the specificity of delivery vehicles for HSCs. The outcome of this study revealed that the VitA-coupled cationic liposomes delivered the TLR4 shRNA to aHSCs more efficiently, as compared to the uncoupled cationic liposomes, both in the in vitro and in vivo conditions. Besides, as evident from the outcome of this study, the TLR4 gene silencing inhibited the HSCs activation and attenuated the liver fibrosis via the NF-κB transcriptional inactivation, pro-inflammatory cytokines secretion and reactive oxygen species (ROS) synthesis. Thus, the VitA-coupled liposomes encapsulated with the TLR4-shRNA might prove as an efficient therapeutic agent for liver fibrosis.
Collapse
Affiliation(s)
- Yuwei Zhang
- Division of Endocrinology and MetabolismState Key Laboratory of BiotherapyWest China HospitalSichuan University, and Collaborative Innovation Center for BiotherapyChengduChina
| | - Yang Li
- Division of Endocrinology and MetabolismState Key Laboratory of BiotherapyWest China HospitalSichuan University, and Collaborative Innovation Center for BiotherapyChengduChina
| | - Tong Mu
- Division of Endocrinology and MetabolismState Key Laboratory of BiotherapyWest China HospitalSichuan University, and Collaborative Innovation Center for BiotherapyChengduChina
| | - Nanwei Tong
- Division of Endocrinology and MetabolismState Key Laboratory of BiotherapyWest China HospitalSichuan University, and Collaborative Innovation Center for BiotherapyChengduChina
| | - Ping Cheng
- State Key Laboratory of Biotherapy and Cancer CenterWest China HospitalSichuan University, and Collaborative Innovation Center for BiotherapyChengduChina
| |
Collapse
|
|
30
|
Leclerc D, Jelinek J, Christensen KE, Issa JPJ, Rozen R. High folic acid intake increases methylation-dependent expression of Lsr and dysregulates hepatic cholesterol homeostasis. J Nutr Biochem 2020; 88:108554. [PMID: 33220403 DOI: 10.1016/j.jnutbio.2020.108554] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2020] [Revised: 09/17/2020] [Accepted: 11/12/2020] [Indexed: 12/12/2022]
Abstract
Food fortification with folic acid and increased use of vitamin supplements have raised concerns about high folic acid intake. We previously showed that high folic acid intake was associated with hepatic degeneration, decreased levels of methylenetetrahydrofolate reductase (MTHFR), lower methylation potential, and perturbations of lipid metabolism. MTHFR synthesizes the folate derivative for methylation reactions. In this study, we assessed the possibility that high folic acid diets, fed to wild-type and Mthfr+/- mice, could alter DNA methylation and/or deregulate hepatic cholesterol homeostasis. Digital restriction enzyme analysis of methylation in liver revealed DNA hypomethylation of a CpG in the lipolysis-stimulated lipoprotein receptor (Lsr) gene, which is involved in hepatic uptake of cholesterol. Pyrosequencing confirmed this methylation change and identified hypomethylation of several neighboring CpG dinucleotides. Lsr expression was increased and correlated negatively with DNA methylation and plasma cholesterol. A putative binding site for E2F1 was identified. ChIP-qPCR confirmed reduced E2F1 binding when methylation at this site was altered, suggesting that it could be involved in increasing Lsr expression. Expression of genes in cholesterol synthesis, transport or turnover (Abcg5, Abcg8, Abcc2, Cyp46a1, and Hmgcs1) was perturbed by high folic acid intake. We also observed increased hepatic cholesterol and increased expression of genes such as Sirt1, which might be involved in a rescue response to restore cholesterol homeostasis. Our work suggests that high folic acid consumption disturbs cholesterol homeostasis in liver. This finding may have particular relevance for MTHFR-deficient individuals, who represent ~10% of many populations.
Collapse
Affiliation(s)
- Daniel Leclerc
- Departments of Human Genetics and Pediatrics, McGill University, Research Institute of the McGill University Health Center, Montreal, Quebec, Canada
| | - Jaroslav Jelinek
- Fels Institute for Cancer Research and Molecular Biology, Temple University, Lewis Katz School of Medicine, Philadelphia, PA, USA
| | - Karen E Christensen
- Departments of Human Genetics and Pediatrics, McGill University, Research Institute of the McGill University Health Center, Montreal, Quebec, Canada
| | - Jean-Pierre J Issa
- Fels Institute for Cancer Research and Molecular Biology, Temple University, Lewis Katz School of Medicine, Philadelphia, PA, USA
| | - Rima Rozen
- Departments of Human Genetics and Pediatrics, McGill University, Research Institute of the McGill University Health Center, Montreal, Quebec, Canada.
| |
Collapse
|
|
31
|
Kyritsi K, Francis H, Zhou T, Ceci L, Wu N, Yang Z, Meng F, Chen L, Baiocchi L, Kundu D, Kennedy L, Liangpunsakul S, Wu C, Glaser S, Alpini G. Downregulation of p16 Decreases Biliary Damage and Liver Fibrosis in the Mdr2 / Mouse Model of Primary Sclerosing Cholangitis. Gene Expr 2020; 20:89-103. [PMID: 32393417 PMCID: PMC7650011 DOI: 10.3727/105221620x15889714507961] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Biliary senescence and hepatic fibrosis are hallmarks of cholangiopathies including primary sclerosing cholangitis (PSC). Senescent cholangiocytes display senescence-associated secretory phenotypes [SASPs, e.g., transforming growth factor-1 (TGF-1)] that further increase biliary senescence (by an autocrine loop) and trigger liver fibrosis by paracrine mechanisms. The aim of this study was to determine the effect of p16 inhibition and role of the TGF-1/microRNA (miR)-34a/sirtuin 1 (SIRT1) axis in biliary damage and liver fibrosis in the Mdr2/ mouse model of PSC. We treated (i) in vivo male wild-type (WT) and Mdr2/ mice with p16 Vivo-Morpholino or controls before measuring biliary mass [intrahepatic bile duct mass (IBDM)] and senescence, biliary SASP levels, and liver fibrosis, and (ii) in vitro intrahepatic murine cholangiocyte lines (IMCLs) with small interfering RNA against p16 before measuring the mRNA expression of proliferation, senescence, and fibrosis markers. p16 and miR-34a increased but SIRT1 decreased in Mdr2/ mice and PSC human liver samples compared to controls. p16 immunoreactivity and biliary senescence and SASP levels increased in Mdr2/ mice but decreased in Mdr2/ mice treated with p16 Vivo-Morpholino. The increase in IBDM and hepatic fibrosis (observed in Mdr2/ mice) returned to normal values in Mdr2/ mice treated with p16 Vivo-Morpholino. TGF-1 immunoreactivity and biliary SASPs levels were higher in Mdr2/ compared to those of WT mice but returned to normal values in Mdr2/ mice treated with p16 Vivo-Morpholino. The expression of fibrosis/senescence markers decreased in cholangiocytes from Mdr2/ mice treated with p16 Vivo-Morpholino (compared to Mdr2/ mice) and in IMCLs (after p16 silencing) compared to controls. Modulation of the TGF-1/miR-34a/SIRT1 axis may be important in the management of PSC phenotypes.
Collapse
Affiliation(s)
| | - Heather Francis
- *Richard L. Roudebush VA Medical Center, Indianapolis, IN, USA
- †Hepatology and Gastroenterology, Medicine, Indiana University, Indianapolis, IN, USA
| | - Tianhao Zhou
- ‡Department of Medical Physiology, Texas A&M University College of Medicine, Bryan, TX, USA
| | - Ludovica Ceci
- *Richard L. Roudebush VA Medical Center, Indianapolis, IN, USA
| | - Nan Wu
- *Richard L. Roudebush VA Medical Center, Indianapolis, IN, USA
| | - Zhihong Yang
- †Hepatology and Gastroenterology, Medicine, Indiana University, Indianapolis, IN, USA
| | - Fanyin Meng
- *Richard L. Roudebush VA Medical Center, Indianapolis, IN, USA
- †Hepatology and Gastroenterology, Medicine, Indiana University, Indianapolis, IN, USA
| | - Lixian Chen
- *Richard L. Roudebush VA Medical Center, Indianapolis, IN, USA
| | - Leonardo Baiocchi
- §Liver Unit, Department of Medicine, University of Rome “Tor Vergata,”Rome, Italy
| | - Debjyoti Kundu
- †Hepatology and Gastroenterology, Medicine, Indiana University, Indianapolis, IN, USA
| | - Lindsey Kennedy
- †Hepatology and Gastroenterology, Medicine, Indiana University, Indianapolis, IN, USA
| | - Suthat Liangpunsakul
- *Richard L. Roudebush VA Medical Center, Indianapolis, IN, USA
- †Hepatology and Gastroenterology, Medicine, Indiana University, Indianapolis, IN, USA
| | - Chaodong Wu
- ¶Department of Nutrition, Texas A&M University, College Station, TX, USA
| | - Shannon Glaser
- ‡Department of Medical Physiology, Texas A&M University College of Medicine, Bryan, TX, USA
| | - Gianfranco Alpini
- *Richard L. Roudebush VA Medical Center, Indianapolis, IN, USA
- †Hepatology and Gastroenterology, Medicine, Indiana University, Indianapolis, IN, USA
| |
Collapse
|
|
32
|
Ceci L, Francis H, Zhou T, Giang T, Yang Z, Meng F, Wu N, Kennedy L, Kyritsi K, Meadows V, Wu C, Liangpunsakul S, Franchitto A, Sybenga A, Ekser B, Mancinelli R, Onori P, Gaudio E, Glaser S, Alpini G. Knockout of the Tachykinin Receptor 1 in the Mdr2 -/- (Abcb4 -/-) Mouse Model of Primary Sclerosing Cholangitis Reduces Biliary Damage and Liver Fibrosis. THE AMERICAN JOURNAL OF PATHOLOGY 2020; 190:2251-2266. [PMID: 32712019 PMCID: PMC7592721 DOI: 10.1016/j.ajpath.2020.07.007] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/10/2020] [Revised: 07/06/2020] [Accepted: 07/08/2020] [Indexed: 12/14/2022]
Abstract
Activation of the substance P (SP)/neurokinin 1 receptor (NK1R) axis triggers biliary damage/senescence and liver fibrosis in bile duct ligated and Mdr2-/- (alias Abcb4-/-) mice through enhanced transforming growth factor-β1 (TGF-β1) biliary secretion. Recent evidence indicates a role for miR-31 (MIR31) in TGF-β1-induced liver fibrosis. We aimed to define the role of the SP/NK1R/TGF-β1/miR-31 axis in regulating biliary proliferation and liver fibrosis during cholestasis. Thus, we generated a novel model with double knockout of Mdr2-/- and NK1R-/ (alias Tacr1-/-) to further address the role of the SP/NK1R axis during chronic cholestasis. In vivo studies were performed in the following 12-week-old male mice: (i) NK1R-/-; (ii) Mdr2-/-; and (iii) NK1R-/-/Mdr2-/- (Tacr1-/-/Abcb4-/-) and their corresponding wild-type controls. Liver tissues and cholangiocytes were collected, and liver damage, changes in biliary mass/senescence, and inflammation as well as liver fibrosis were evaluated by both immunohistochemistry in liver sections and real-time PCR. miR-31 expression was measured by real-time PCR in isolated cholangiocytes. Decreased ductular reaction, liver fibrosis, biliary senescence, and biliary inflammation were observed in NK1R-/-/Mdr2-/- mice compared with Mdr2-/- mice. Elevated expression of miR-31 was observed in Mdr2-/- mice, which was reduced in NK1R-/-/Mdr2-/- mice. Targeting the SP/NK1R and/or miR-31 may be a potential approach in treating human cholangiopathies, including primary sclerosing cholangitis.
Collapse
Affiliation(s)
- Ludovica Ceci
- Division of Hepatology and Gastroenterology, Medicine, Indiana University, Indianapolis, Indiana
| | - Heather Francis
- Division of Hepatology and Gastroenterology, Medicine, Indiana University, Indianapolis, Indiana; Richard L. Roudebush VA Medical Center, Indianapolis, Indiana
| | - Tianhao Zhou
- Department of Medical Physiology, Texas A&M University, Bryan, Texas
| | - Thao Giang
- Department of Medical Physiology, Texas A&M University, Bryan, Texas
| | - Zhihong Yang
- Division of Hepatology and Gastroenterology, Medicine, Indiana University, Indianapolis, Indiana
| | - Fanyin Meng
- Division of Hepatology and Gastroenterology, Medicine, Indiana University, Indianapolis, Indiana; Richard L. Roudebush VA Medical Center, Indianapolis, Indiana
| | - Nan Wu
- Division of Hepatology and Gastroenterology, Medicine, Indiana University, Indianapolis, Indiana
| | - Lindsey Kennedy
- Division of Hepatology and Gastroenterology, Medicine, Indiana University, Indianapolis, Indiana
| | - Konstantina Kyritsi
- Division of Hepatology and Gastroenterology, Medicine, Indiana University, Indianapolis, Indiana
| | - Vik Meadows
- Division of Hepatology and Gastroenterology, Medicine, Indiana University, Indianapolis, Indiana
| | - Chaodong Wu
- Department of Nutrition, Texas A&M University, College Station, Texas
| | - Suthat Liangpunsakul
- Division of Hepatology and Gastroenterology, Medicine, Indiana University, Indianapolis, Indiana; Richard L. Roudebush VA Medical Center, Indianapolis, Indiana
| | | | - Amelia Sybenga
- Department of Pathology and Laboratory Medicine, University of Vermont Medical Center, Burlington, Vermont
| | - Burcin Ekser
- Division of Transplant Surgery, Department of Surgery, Indiana University, Indianapolis, Indiana
| | - Romina Mancinelli
- Department of Anatomical, Histological, Forensic Medicine and Orthopedics Sciences, Sapienza University of Rome, Rome, Italy
| | - Paolo Onori
- Department of Anatomical, Histological, Forensic Medicine and Orthopedics Sciences, Sapienza University of Rome, Rome, Italy
| | - Eugenio Gaudio
- Department of Anatomical, Histological, Forensic Medicine and Orthopedics Sciences, Sapienza University of Rome, Rome, Italy
| | - Shannon Glaser
- Department of Medical Physiology, Texas A&M University, Bryan, Texas
| | - Gianfranco Alpini
- Division of Hepatology and Gastroenterology, Medicine, Indiana University, Indianapolis, Indiana; Richard L. Roudebush VA Medical Center, Indianapolis, Indiana.
| |
Collapse
|
|
33
|
Fourman LT, Billingsley JM, Agyapong G, Ho Sui SJ, Feldpausch MN, Purdy J, Zheng I, Pan CS, Corey KE, Torriani M, Kleiner DE, Hadigan CM, Stanley TL, Chung RT, Grinspoon SK. Effects of tesamorelin on hepatic transcriptomic signatures in HIV-associated NAFLD. JCI Insight 2020; 5:140134. [PMID: 32701508 PMCID: PMC7455119 DOI: 10.1172/jci.insight.140134] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2020] [Accepted: 07/15/2020] [Indexed: 12/12/2022] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is a common comorbidity among people living with HIV that has a more aggressive course than NAFLD among the general population. In a recent randomized placebo-controlled trial, we demonstrated that the growth hormone-releasing hormone analog tesamorelin reduced liver fat and prevented fibrosis progression in HIV-associated NAFLD over 1 year. As such, tesamorelin is the first strategy that has shown to be effective against NAFLD among the population with HIV. The current study leveraged paired liver biopsy specimens from this trial to identify hepatic gene pathways that are differentially modulated by tesamorelin versus placebo. Using gene set enrichment analysis, we found that tesamorelin increased hepatic expression of hallmark gene sets involved in oxidative phosphorylation and decreased hepatic expression of gene sets contributing to inflammation, tissue repair, and cell division. Tesamorelin also reciprocally up- and downregulated curated gene sets associated with favorable and poor hepatocellular carcinoma prognosis, respectively. Notably, among tesamorelin-treated participants, these changes in hepatic expression correlated with improved fibrosis-related gene score. Our findings inform our knowledge of the biology of pulsatile growth hormone action and provide a mechanistic basis for the observed clinical effects of tesamorelin on the liver.
Collapse
Affiliation(s)
- Lindsay T Fourman
- Metabolism Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA
| | - James M Billingsley
- Harvard Chan Bioinformatics Core, Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA
| | - George Agyapong
- Liver Center, Digestive Healthcare Center, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA
| | - Shannan J Ho Sui
- Harvard Chan Bioinformatics Core, Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA
| | - Meghan N Feldpausch
- Metabolism Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA
| | - Julia Purdy
- National Institute of Allergy and Infectious Diseases, NIH, Bethesda, Maryland, USA
| | - Isabel Zheng
- Metabolism Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA
| | - Chelsea S Pan
- Metabolism Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA
| | - Kathleen E Corey
- Liver Center, Digestive Healthcare Center, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA
| | - Martin Torriani
- Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA
| | - David E Kleiner
- Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland, USA
| | - Colleen M Hadigan
- National Institute of Allergy and Infectious Diseases, NIH, Bethesda, Maryland, USA
| | - Takara L Stanley
- Metabolism Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA
| | - Raymond T Chung
- Liver Center, Digestive Healthcare Center, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA
| | - Steven K Grinspoon
- Metabolism Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA
| |
Collapse
|
|
34
|
E2F1 Regulates Adipocyte Differentiation and Adipogenesis by Activating ICAT. Cells 2020; 9:cells9041024. [PMID: 32326181 PMCID: PMC7225968 DOI: 10.3390/cells9041024] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2020] [Revised: 03/25/2020] [Accepted: 04/07/2020] [Indexed: 02/06/2023] Open
Abstract
Wnt/β-catenin is a crucial repressor of adipogenesis. We have shown that E2 promoter binding factor 1 (E2F1) suppresses Wnt/β-catenin activity through transactivation of β-catenin interacting protein 1 (CTNNBIP1), also known as inhibitor of β-catenin and TCF4 (ICAT) in human colorectal cancers. However, it remains unknown whether ICAT is required for E2F1 to promote differentiation by inhibiting β-catenin activity in pre-adipocytes. In the present study, we found that 1-methyl-3-isobutylxanthine, dexamethasone, and insulin (MDI)-induced differentiation and lipid accumulation in 3T3-L1 pre-adipocytes was reversed by activation of β-catenin triggered by CHIR99021, a GSK3β inhibitor. Intriguingly, we observed a reduced protein level of E2F1 and ICAT at a later stage of pre-adipocytes differentiation. Importantly, overexpression of ICAT in 3T3-L1 pre-adipocytes markedly promote the adipogenesis and partially reversed the inhibitory effect of CHIR99021 on MDI-induced adipogenesis and lipid accumulation by regulating adipogenic regulators and Wnt/β-catenin targets. Moreover, pre-adipocytes differentiation induced by MDI were markedly inhibited in siE2F1 or siICAT transfected 3T3-L1 cells. Gene silencing of ICAT in the E2F1 overexpressed adipocytes also inhibited the adipogenesis. These data indicated that E2F1 is a metabolic regulator with an ability to promote pre-adipocyte differentiation by activating ICAT, therefore represses Wnt/β-catenin activity in 3T3-L1 cells. We also demonstrated that ICAT overexpression did not affect oleic acid-induced lipid accumulation at the surface of Hela and HepG2 cells. In conclusion, we show that E2F1 is a critical regulator with an ability to promote differentiation and adipogenesis by activating ICAT in pre-adipocytes.
Collapse
|
|
35
|
Kyritsi K, Chen L, O’Brien A, Francis H, Hein TW, Venter J, Wu N, Ceci L, Zhou T, Zawieja D, Gashev AA, Meng F, Invernizzi P, Fabris L, Wu C, Skill NJ, Saxena R, Liangpunsakul S, Alpini G, Glaser SS. Modulation of the Tryptophan Hydroxylase 1/Monoamine Oxidase-A/5-Hydroxytryptamine/5-Hydroxytryptamine Receptor 2A/2B/2C Axis Regulates Biliary Proliferation and Liver Fibrosis During Cholestasis. Hepatology 2020; 71:990-1008. [PMID: 31344280 PMCID: PMC6993623 DOI: 10.1002/hep.30880] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/13/2018] [Accepted: 07/19/2019] [Indexed: 12/28/2022]
Abstract
BACKGROUND AND AIMS Serotonin (5HT) is a neuroendocrine hormone synthetized in the central nervous system (CNS) as well as enterochromaffin cells of the gastrointestinal tract. Tryptophan hydroxylase (TPH1) and monoamine oxidase (MAO-A) are the key enzymes for the synthesis and catabolism of 5HT, respectively. Previous studies demonstrated that 5-hydroxytryptamine receptor (5HTR)1A/1B receptor agonists inhibit biliary hyperplasia in bile-duct ligated (BDL) rats, whereas 5HTR2B receptor antagonists attenuate liver fibrosis (LF) in mice. Our aim was to evaluate the role of 5HTR2A/2B/2C agonists/antagonists in cholestatic models. APPROACH AND RESULTS While in vivo studies were performed in BDL rats and the multidrug resistance gene 2 knockout (Mdr2-/- ) mouse model of PSC, in vitro studies were performed in cell lines of cholangiocytes and hepatic stellate cells (HSCs). 5HTR2A/2B/2C and MAO-A/TPH1 are expressed in cholangiocytes and HSCs from BDL rats and Mdr2-/- - mice. Ductular reaction, LF, as well as the mRNA expression of proinflammatory genes increased in normal, BDL rats, and Mdr2-/- - mice following treatment 5HTR2A/2B/2C agonists, but decreased when BDL rats and Mdr2-/- mice were treated with 5HTR2A/2B/2C antagonists compared to BDL rats and Mdr2-/- mice, respectively. 5HT levels increase in Mdr2-/- mice and in PSC human patients compared to their controls and decrease in serum of Mdr2-/- mice treated with 5HTR2A/2B/2C antagonists compared to untreated Mdr2-/- mice. In vitro, cell lines of murine cholangiocytes and human HSCs express 5HTR2A/2B/2C and MAO-A/TPH1; treatment of these cell lines with 5HTR2A/2B/2C antagonists or TPH1 inhibitor decreased 5HT levels as well as expression of fibrosis and inflammation genes compared to controls. CONCLUSIONS Modulation of the TPH1/MAO-A/5HT/5HTR2A/2B/2C axis may represent a therapeutic approach for management of cholangiopathies, including PSC.
Collapse
MESH Headings
- ATP Binding Cassette Transporter, Subfamily B/physiology
- Animals
- Bile Ducts/pathology
- Cell Proliferation
- Cholangitis, Sclerosing/etiology
- Cholestasis/pathology
- Humans
- Liver Cirrhosis/etiology
- Male
- Mice
- Monoamine Oxidase/physiology
- Rats
- Rats, Sprague-Dawley
- Receptor, Serotonin, 5-HT2A/physiology
- Receptor, Serotonin, 5-HT2B/physiology
- Receptor, Serotonin, 5-HT2C/physiology
- Receptors, Serotonin/physiology
- Serotonin/blood
- Serotonin/physiology
- Tryptophan Hydroxylase/physiology
- ATP-Binding Cassette Sub-Family B Member 4
Collapse
Affiliation(s)
- Konstantina Kyritsi
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN
| | - Lixian Chen
- Department of Medical Physiology, Texas A&M University College of Medicine, Bryan, TX
| | - April O’Brien
- Department of Medical Physiology, Texas A&M University College of Medicine, Bryan, TX
| | - Heather Francis
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN
- Indiana University School of Medicine, Research, Richard L. Roudebush VA Medical Center, Indianapolis, IN
| | - Travis W. Hein
- Department of Medical Physiology, Texas A&M University College of Medicine, Bryan, TX
| | - Julie Venter
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN
| | - Nan Wu
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN
| | - Ludovica Ceci
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN
| | - Tianhao Zhou
- Department of Medical Physiology, Texas A&M University College of Medicine, Bryan, TX
| | - David Zawieja
- Department of Medical Physiology, Texas A&M University College of Medicine, Bryan, TX
| | - Anatoliy A. Gashev
- Department of Medical Physiology, Texas A&M University College of Medicine, Bryan, TX
| | - Fanyin Meng
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN
- Indiana University School of Medicine, Research, Richard L. Roudebush VA Medical Center, Indianapolis, IN
| | - Pietro Invernizzi
- Humanitas Clinical and Research Center, Rozzano (MI), Italy
- Division of Rheumatology, Allergy, and Clinical Immunology, University of California at Davis, Davis, CA
| | - Luca Fabris
- Department of Molecular Medicine, University of Padua School of Medicine, Padua, Italy
- Digestive Disease Section, Yale University School of Medicine, New Haven, CT
| | - Chaodong Wu
- Department of Nutrition and Food Science, Texas A&M University, College Station, TX
| | - Nicholas J. Skill
- Department of Surgery, Indiana University School of Medicine, Indianapolis, IN
| | - Romil Saxena
- Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN
| | - Suthat Liangpunsakul
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN
- Indiana University School of Medicine, Research, Richard L. Roudebush VA Medical Center, Indianapolis, IN
| | - Gianfranco Alpini
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN
- Indiana University School of Medicine, Research, Richard L. Roudebush VA Medical Center, Indianapolis, IN
| | - Shannon S. Glaser
- Department of Medical Physiology, Texas A&M University College of Medicine, Bryan, TX
| |
Collapse
|
|
36
|
Inflammation: Cause or consequence of chronic cholestatic liver injury. Food Chem Toxicol 2020; 137:111133. [PMID: 31972189 DOI: 10.1016/j.fct.2020.111133] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2019] [Revised: 12/04/2019] [Accepted: 01/14/2020] [Indexed: 12/12/2022]
Abstract
Cholestasis is a result of obstruction of the biliary tracts. It is a common cause of liver pathology after exposure to toxic xenobiotics and during numerous other liver diseases. Accumulation of bile acids in the liver is thought to be a major driver of liver injury during cholestasis and can lead to eventual liver fibrosis and cirrhosis. As such, current therapy in the field of chronic liver diseases with prominent cholestasis relies heavily on increasing choleresis to limit accumulation of bile acids. Many of these same diseases also present with autoimmunity before the onset of cholestasis though, indicating the inflammation may be an initiating component of the pathology. Moreover, cytotoxic inflammatory mediators accumulate during cholestasis and can propagate liver injury. Anti-inflammatory biologics and small molecules have largely failed clinical trials in these diseases though and as such, targeting inflammation as a means to address cholestatic liver injury remains debatable. The purpose of this review is to understand the different roles that inflammation can play during cholestatic liver injury and attempt to define how new therapeutic targets that limit or control inflammation may be beneficial for patients with chronic cholestatic liver disease.
Collapse
|
|
37
|
Zhang TN, Wang W, Yang N, Huang XM, Liu CF. Regulation of Glucose and Lipid Metabolism by Long Non-coding RNAs: Facts and Research Progress. Front Endocrinol (Lausanne) 2020; 11:457. [PMID: 32765426 PMCID: PMC7381111 DOI: 10.3389/fendo.2020.00457] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/11/2020] [Accepted: 06/10/2020] [Indexed: 12/17/2022] Open
Abstract
Long non-coding RNAs (lncRNAs) are a type of non-coding RNA with a length that exceeds 200 nucleotides. Previous studies have shown that lncRNAs play an important role in the pathogenesis of various diseases. Research in both animal models and humans has begun to unravel the profound complexity of lncRNAs and demonstrated that lncRNAs exert direct effects on glucose and lipid metabolism both in vivo and in vitro. Such research has elucidated the regulatory role of lncRNAs in glucose and lipid metabolism in human disease. lncRNAs mediate glucose and lipid metabolism under physiological and pathological conditions and contribute to various metabolism disorders. This review provides an update on our understanding of the regulatory role of lncRNAs in glucose and lipid metabolism in various diseases. As our understanding of the function of lncRNAs improves, the future is promising for the development of new diagnostic biomarkers that utilize lncRNAs and treatments that target lncRNAs to improve clinical outcomes.
Collapse
Affiliation(s)
- Tie-Ning Zhang
- Department of Pediatrics, Shengjing Hospital of China Medical University, Shenyang, China
- *Correspondence: Tie-Ning Zhang
| | - Wei Wang
- Department of Pediatrics, Shengjing Hospital of China Medical University, Shenyang, China
| | - Ni Yang
- Department of Pediatrics, Shengjing Hospital of China Medical University, Shenyang, China
| | - Xin-Mei Huang
- Department of Endocrinology, the Fifth People's Hospital of Shanghai, Fudan University, Shanghai, China
- Department of Obstetrics and Gynecology, Yale University School of Medicine, New Haven, CT, United States
- Xin-Mei Huang
| | - Chun-Feng Liu
- Department of Pediatrics, Shengjing Hospital of China Medical University, Shenyang, China
- Chun-Feng Liu
| |
Collapse
|
|
38
|
Magee N, Zou A, Ghosh P, Ahamed F, Delker D, Zhang Y. Disruption of hepatic small heterodimer partner induces dissociation of steatosis and inflammation in experimental nonalcoholic steatohepatitis. J Biol Chem 2020. [DOI: 10.1016/s0021-9258(17)49910-8] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
|
|
39
|
Magee N, Zou A, Ghosh P, Ahamed F, Delker D, Zhang Y. Disruption of hepatic small heterodimer partner induces dissociation of steatosis and inflammation in experimental nonalcoholic steatohepatitis. J Biol Chem 2019; 295:994-1008. [PMID: 31831621 DOI: 10.1074/jbc.ra119.010233] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2019] [Revised: 11/23/2019] [Indexed: 12/16/2022] Open
Abstract
Nonalcoholic steatohepatitis (NASH) is a leading cause of chronic liver disease worldwide and is characterized by steatosis, inflammation, and fibrosis. The molecular mechanisms underlying NASH development remain obscure. The nuclear receptor small heterodimer partner (Shp) plays a complex role in lipid metabolism and inflammation. Here, we sought to determine SHP's role in regulating steatosis and inflammation in NASH. Shp deletion in murine hepatocytes (Shp Hep-/-) resulted in massive infiltration of macrophages and CD4+ T cells in the liver. Shp Hep-/- mice developed reduced steatosis, but surprisingly increased hepatic inflammation and fibrosis after being fed a high-fat, -cholesterol, and -fructose (HFCF) diet. RNA-Seq analysis revealed that pathways involved in inflammation and fibrosis are significantly activated in the liver of Shp Hep-/- mice fed a chow diet. After having been fed the HFCF diet, WT mice displayed up-regulated peroxisome proliferator-activated receptor γ (Pparg) signaling in the liver; however, this response was completely abolished in the Shp Hep-/- mice. In contrast, livers of Shp Hep-/- mice had consistent NF-κB activation. To further characterize the role of Shp specifically in the transition of steatosis to NASH, mice were fed the HFCF diet for 4 weeks, followed by Shp deletion. Surprisingly, Shp deletion after steatosis development exacerbated hepatic inflammation and fibrosis without affecting liver steatosis. Together, our results indicate that, depending on NASH stage, hepatic Shp plays an opposing role in steatosis and inflammation. Mechanistically, Shp deletion in hepatocytes activated NF-κB and impaired Pparg activation, leading to the dissociation of steatosis, inflammation, and fibrosis in NASH development.
Collapse
Affiliation(s)
- Nancy Magee
- Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas 66160
| | - An Zou
- Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas 66160
| | - Priyanka Ghosh
- Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas 66160
| | - Forkan Ahamed
- Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas 66160
| | - Don Delker
- Department of Medicine, University of Utah School of Medicine, Salt Lake City, Utah 84108
| | - Yuxia Zhang
- Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas 66160 .,Liver Center, University of Kansas Medical Center, Kansas City, Kansas 66160
| |
Collapse
|
|
40
|
Yu MC, Liu JX, Ma XL, Hu B, Fu PY, Sun HX, Tang WG, Yang ZF, Qiu SJ, Zhou J, Fan J, Xu Y. Differential network analysis depicts regulatory mechanisms for hepatocellular carcinoma from diverse backgrounds. Future Oncol 2019; 15:3917-3934. [PMID: 31729887 DOI: 10.2217/fon-2019-0275] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
Aim: To elucidate the integrative combinational gene regulatory network landscape of hepatocellular carcinoma (HCC) molecular carcinogenesis from diverse background. Materials & methods: Modified gene regulatory network analysis was used to prioritize differentially regulated genes and links. Integrative comparisons using bioinformatics methods were applied to identify potential critical molecules and pathways in HCC with different backgrounds. Results: E2F1 with its surrounding regulatory links were identified to play different key roles in the HCC risk factor dysregulation mechanisms. Hsa-mir-19a was identified as showed different effects in the three HCC differential regulation networks, and showed vital regulatory role in HBV-related HCC. Conclusion: We describe in detail the regulatory networks involved in HCC with different backgrounds. E2F1 may serve as a universal target for HCC treatment.
Collapse
Affiliation(s)
- Min-Cheng Yu
- Department of Liver Surgery & Transplantation, Zhongshan Hospital, Fudan University; Key Laboratory of Carcinogenesis & Cancer Invasion (Fudan University), Ministry of Education, Shanghai 200032, PR China
| | - Ji-Xiang Liu
- Shanghai Center for Bioinformation Technology & Shanghai Engineering Research Center of Pharmaceutical Translation, Shanghai Industrial Technology Institute, 1278 Keyuan Road, Shanghai 201203, PR China
| | - Xiao-Lu Ma
- Department of Laboratory Medicine, Shanghai Cancer Center, Fudan University, Shanghai 200032, PR China
| | - Bo Hu
- Department of Liver Surgery & Transplantation, Zhongshan Hospital, Fudan University; Key Laboratory of Carcinogenesis & Cancer Invasion (Fudan University), Ministry of Education, Shanghai 200032, PR China
| | - Pei-Yao Fu
- Department of Liver Surgery & Transplantation, Zhongshan Hospital, Fudan University; Key Laboratory of Carcinogenesis & Cancer Invasion (Fudan University), Ministry of Education, Shanghai 200032, PR China
| | - Hai-Xiang Sun
- Department of Liver Surgery & Transplantation, Zhongshan Hospital, Fudan University; Key Laboratory of Carcinogenesis & Cancer Invasion (Fudan University), Ministry of Education, Shanghai 200032, PR China
| | - Wei-Guo Tang
- Institute of Fudan-Minhang Academic Health System, Minhang Hospital, Fudan University, Shanghai 201199, PR China
| | - Zhang-Fu Yang
- Department of Liver Surgery & Transplantation, Zhongshan Hospital, Fudan University; Key Laboratory of Carcinogenesis & Cancer Invasion (Fudan University), Ministry of Education, Shanghai 200032, PR China
| | - Shuang-Jian Qiu
- Department of Liver Surgery & Transplantation, Zhongshan Hospital, Fudan University; Key Laboratory of Carcinogenesis & Cancer Invasion (Fudan University), Ministry of Education, Shanghai 200032, PR China
| | - Jian Zhou
- Department of Liver Surgery & Transplantation, Zhongshan Hospital, Fudan University; Key Laboratory of Carcinogenesis & Cancer Invasion (Fudan University), Ministry of Education, Shanghai 200032, PR China.,State Key Laboratory of Genetic Engineering, Fudan University, Shanghai 200032, PR China.,Institute of Biomedical Sciences, Fudan University, Shanghai 200032, PR China
| | - Jia Fan
- Department of Liver Surgery & Transplantation, Zhongshan Hospital, Fudan University; Key Laboratory of Carcinogenesis & Cancer Invasion (Fudan University), Ministry of Education, Shanghai 200032, PR China.,State Key Laboratory of Genetic Engineering, Fudan University, Shanghai 200032, PR China.,Institute of Biomedical Sciences, Fudan University, Shanghai 200032, PR China
| | - Yang Xu
- Department of Liver Surgery & Transplantation, Zhongshan Hospital, Fudan University; Key Laboratory of Carcinogenesis & Cancer Invasion (Fudan University), Ministry of Education, Shanghai 200032, PR China
| |
Collapse
|
|
41
|
Zhou T, Kyritsi K, Wu N, Francis H, Yang Z, Chen L, O'Brien A, Kennedy L, Ceci L, Meadows V, Kusumanchi P, Wu C, Baiocchi L, Skill NJ, Saxena R, Sybenga A, Xie L, Liangpunsakul S, Meng F, Alpini G, Glaser S. Knockdown of vimentin reduces mesenchymal phenotype of cholangiocytes in the Mdr2 -/- mouse model of primary sclerosing cholangitis (PSC). EBioMedicine 2019; 48:130-142. [PMID: 31522982 PMCID: PMC6838376 DOI: 10.1016/j.ebiom.2019.09.013] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2019] [Revised: 09/02/2019] [Accepted: 09/06/2019] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Cholangiocytes are the target cells of cholangiopathies including primary sclerosing cholangitis (PSC). Vimentin is an intermediate filament protein that has been found in various types of mesenchymal cells. The aim of this study is to evaluate the role of vimentin in the progression of biliary damage/liver fibrosis and whether there is a mesenchymal phenotype of cholangiocytes in the Mdr2-/- model of PSC. METHODS In vivo studies were performed in 12 wk. Mdr2-/- male mice with or without vimentin Vivo-Morpholino treatment and their corresponding control groups. Liver specimens from human PSC patients, human intrahepatic biliary epithelial cells (HIBEpiC) and human hepatic stellate cell lines (HHSteCs) were used to measure changes in epithelial-to-mesenchymal transition (EMT). FINDINGS There was increased mesenchymal phenotype of cholangiocytes in Mdr2-/- mice, which was reduced by treatment of vimentin Vivo-Morpholino. Concomitant with reduced vimentin expression, there was decreased liver damage, ductular reaction, biliary senescence, liver fibrosis and TGF-β1 secretion in Mdr2-/- mice treated with vimentin Vivo-Morpholino. Human PSC patients and derived cell lines had increased expression of vimentin and other mesenchymal markers compared to healthy controls and HIBEpiC, respectively. In vitro silencing of vimentin in HIBEpiC suppressed TGF-β1-induced EMT and fibrotic reaction. HHSteCs had decreased fibrotic reaction and increased cellular senescence after stimulation with cholangiocyte supernatant with reduced vimentin levels. INTERPRETATION Our study demonstrated that knockdown of vimentin reduces mesenchymal phenotype of cholangiocytes, which leads to decreased biliary senescence and liver fibrosis. Inhibition of vimentin may be a key therapeutic target in the treatment of cholangiopathies including PSC. FUND: National Institutes of Health (NIH) awards, VA Merit awards.
Collapse
Affiliation(s)
- Tianhao Zhou
- Department of Medical Physiology, College of Medicine, Texas A&M University, Bryan, TX, United States of America
| | - Konstantina Kyritsi
- Gastroenterology, Medicine, Indiana University, Indianapolis, IN, United States of America
| | - Nan Wu
- Gastroenterology, Medicine, Indiana University, Indianapolis, IN, United States of America
| | - Heather Francis
- Richard L. Roudebush VA Medical Center, Indianapolis, IN, United States of America; Gastroenterology, Medicine, Indiana University, Indianapolis, IN, United States of America
| | - Zhihong Yang
- Richard L. Roudebush VA Medical Center, Indianapolis, IN, United States of America; Gastroenterology, Medicine, Indiana University, Indianapolis, IN, United States of America
| | - Lixian Chen
- Department of Medical Physiology, College of Medicine, Texas A&M University, Bryan, TX, United States of America
| | - April O'Brien
- Department of Medical Physiology, College of Medicine, Texas A&M University, Bryan, TX, United States of America
| | - Lindsey Kennedy
- Gastroenterology, Medicine, Indiana University, Indianapolis, IN, United States of America
| | - Ludovica Ceci
- Gastroenterology, Medicine, Indiana University, Indianapolis, IN, United States of America
| | - Vik Meadows
- Gastroenterology, Medicine, Indiana University, Indianapolis, IN, United States of America
| | - Praveen Kusumanchi
- Richard L. Roudebush VA Medical Center, Indianapolis, IN, United States of America; Gastroenterology, Medicine, Indiana University, Indianapolis, IN, United States of America
| | - Chaodong Wu
- Department of Nutrition and Food Science, College of Medicine, Texas A&M University, United States of America
| | | | - Nicholas J Skill
- Department of Surgery, Indiana University, Indianapolis, IN, United States of America
| | - Romil Saxena
- Department of Pathology, Indiana University, Indianapolis, IN, United States of America
| | - Amelia Sybenga
- Department of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, TN, United States of America
| | - Linglin Xie
- Department of Nutrition and Food Science, College of Medicine, Texas A&M University, United States of America
| | - Suthat Liangpunsakul
- Richard L. Roudebush VA Medical Center, Indianapolis, IN, United States of America; Gastroenterology, Medicine, Indiana University, Indianapolis, IN, United States of America
| | - Fanyin Meng
- Richard L. Roudebush VA Medical Center, Indianapolis, IN, United States of America; Gastroenterology, Medicine, Indiana University, Indianapolis, IN, United States of America
| | - Gianfranco Alpini
- Richard L. Roudebush VA Medical Center, Indianapolis, IN, United States of America; Gastroenterology, Medicine, Indiana University, Indianapolis, IN, United States of America.
| | - Shannon Glaser
- Department of Medical Physiology, College of Medicine, Texas A&M University, Bryan, TX, United States of America.
| |
Collapse
|
|
42
|
Li YK, Li YM, Li Y, Wei YR, Zhang J, Li B, You ZR, Chen Y, Huang BY, Miao Q, Wang QX, Peng YS, Gershwin ME, Tang RQ, Bian ZL, Ma X. CTHRC1 expression in primary biliary cholangitis. J Dig Dis 2019; 20:371-376. [PMID: 31102333 DOI: 10.1111/1751-2980.12791] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/14/2019] [Accepted: 05/07/2019] [Indexed: 12/11/2022]
Abstract
OBJECTIVES Collagen triple helix repeat containing-1 (CTHRC1) is a highly conserved extracellular matrix glycoprotein that is overexpressed in two murine models of cholestatic liver fibrosis. Elevated CTHRC1 has been found to attenuate liver fibrosis in these murine models, thus we aimed to study the expression of CTHRC1 in patients with cholestatic liver diseases and its correlation with hepatic conditions. METHODS Ninety patients with chronic liver disease, including 48 had primary biliary cholangitis (PBC), 18 had primary sclerosing cholangitis (PSC) and 24 had chronic hepatitis B (CHB), together with five healthy controls (HC), were recruited to this study. Participants' liver sections were analyzed using immunohistochemistry. Serum CTHRC1 levels in another cohort of 59 patients with PBC and 10 age-matched HC were detected by enzyme-linked immunosorbent assay. RESULTS CTHRC1 protein was primarily expressed in activated hepatic stellate cells (HSC). CTHRC1 expression was significantly increased in the PBC and PSC groups, compared with the HC and CHB groups. Importantly, the hepatic fibrosis stage of the PBC group was positively correlated with hepatic CTHRC1 expression (r = 0.425, P = 0.003). Meanwhile, there were significant correlations between serum CTHRC1 levels and both the degrees of hepatic inflammation and fibrosis stage in the PBC group (r = 0.300, P = 0.022; r = 0.321, P = 0.012). CONCLUSION CTHRC1 may play a role in hepatic fibrogenesis in PBC and that serum CTHRC1 may be a potential novel noninvasive biomarker in the assessment of liver fibrosis and inflammation.
Collapse
Affiliation(s)
- Yi Kang Li
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory for Oncogenes and Related Genes; Shanghai Institute of Digestive Disease; Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Yan Mei Li
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory for Oncogenes and Related Genes; Shanghai Institute of Digestive Disease; Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - You Li
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory for Oncogenes and Related Genes; Shanghai Institute of Digestive Disease; Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Yi Ran Wei
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory for Oncogenes and Related Genes; Shanghai Institute of Digestive Disease; Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Jun Zhang
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory for Oncogenes and Related Genes; Shanghai Institute of Digestive Disease; Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Bo Li
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory for Oncogenes and Related Genes; Shanghai Institute of Digestive Disease; Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Zheng Rui You
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory for Oncogenes and Related Genes; Shanghai Institute of Digestive Disease; Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Yong Chen
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory for Oncogenes and Related Genes; Shanghai Institute of Digestive Disease; Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Bing Yuan Huang
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory for Oncogenes and Related Genes; Shanghai Institute of Digestive Disease; Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Qi Miao
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory for Oncogenes and Related Genes; Shanghai Institute of Digestive Disease; Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Qi Xia Wang
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory for Oncogenes and Related Genes; Shanghai Institute of Digestive Disease; Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Yan Shen Peng
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory for Oncogenes and Related Genes; Shanghai Institute of Digestive Disease; Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - M Eric Gershwin
- Division of Rheumatology, Allergy, and Clinical Immunology, University of California at Davis, Davis, CA, USA
| | - Ru Qi Tang
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory for Oncogenes and Related Genes; Shanghai Institute of Digestive Disease; Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Zhao Lian Bian
- Department of Gastroenterology and Hepatology, Nantong Institute of Liver Disease, Nantong Third People's Hospital, Nantong University, Nantong, Jiangsu Province, China
| | - Xiong Ma
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory for Oncogenes and Related Genes; Shanghai Institute of Digestive Disease; Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| |
Collapse
|
|
43
|
Zhou J, Huang N, Guo Y, Cui S, Ge C, He Q, Pan X, Wang G, Wang H, Hao H. Combined obeticholic acid and apoptosis inhibitor treatment alleviates liver fibrosis. Acta Pharm Sin B 2019; 9:526-536. [PMID: 31193776 PMCID: PMC6542786 DOI: 10.1016/j.apsb.2018.11.004] [Citation(s) in RCA: 64] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2018] [Revised: 10/21/2018] [Accepted: 10/22/2018] [Indexed: 01/06/2023] Open
Abstract
Obeticholic acid (OCA), the first FXR-targeting drug, has been claimed effective in the therapy of liver fibrosis. However, recent clinical trials indicated that OCA might not be effective against liver fibrosis, possibly due to the lower dosage to reduce the incidence of the side-effect of pruritus. Here we propose a combinatory therapeutic strategy of OCA and apoptosis inhibitor for combating against liver fibrosis. CCl4-injured mice, d-galactosamine/LPS (GalN/LPS)-treated mice and cycloheximide/TNFα (CHX/TNFα)-treated HepG2 cells were employed to assess the effects of OCA, or together with IDN-6556, an apoptosis inhibitor. OCA treatment significantly inhibited hepatic stellate cell (HSC) activation/proliferation and prevented fibrosis. Elevated bile acid (BA) levels and hepatocyte apoptosis triggered the activation and proliferation of HSCs. OCA treatment reduced BA levels but could not inhibit hepatocellular apoptosis. An enhanced anti-fibrotic effect was observed when OCA was co-administrated with IDN-6556. Our study demonstrated that OCA inhibits HSCs activation/proliferation partially by regulating BA homeostasis and thereby inhibiting activation of HSCs. The findings in this study suggest that combined use of apoptosis inhibitor and OCA at lower dosage represents a novel therapeutic strategy for liver fibrosis.
Collapse
Key Words
- ALT, alanine aminotransferase
- ANOVA, analysis of variance
- AST, aspartate aminotransferase
- BA, bile acid
- BSEP, bile salt export pump
- Bile acid
- BrdU, bromodeoxyuridine
- CA, cholic acid
- CCl4, carbon tetrachloride
- CDCA, chenodeoxycholic acid
- CHX, cycloheximide
- CYP7A1, cholesterol 7α-hydroxylase
- Col, collagen
- FXR, farnesoid X receptor
- Farnesoid X receptor
- GalN, d-galactosamine
- H&E, hematoxylin and eosin
- HPLC, high performance liquid chromatography
- HSCs, hepatic stellate cells
- Hepatic stellate cell
- Hepatocellular apoptosis
- IDN-6556
- KCs, Kupffer cells
- LPS, lipopolysaccharide
- Liver fibrosis
- OCA, obeticholic acid
- Obeticholic acid
- PBC, primary biliary cholangitis
- RT-PCR, reverse transcription polymerase chain reaction
- SHP, small heterodimer partner
- TGF, transforming growth factor
- TIMP, tissue inhibitor of metalloproteinase
- TNFα, tumor necrosis factor α
- TUNEL, terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling
- α-SMA, α-smooth muscle action
Collapse
Affiliation(s)
- Jiyu Zhou
- State Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing 210009, China
| | - Ningning Huang
- State Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing 210009, China
| | - Yitong Guo
- State Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing 210009, China
| | - Shuang Cui
- State Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing 210009, China
| | - Chaoliang Ge
- State Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing 210009, China
- First Affiliated Hospital of Anhui Medical University, Hefei 230022, China
| | - Qingxian He
- State Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing 210009, China
| | - Xiaojie Pan
- State Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing 210009, China
| | - Guangji Wang
- State Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing 210009, China
| | - Hong Wang
- State Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing 210009, China
| | - Haiping Hao
- State Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing 210009, China
| |
Collapse
|
|
44
|
Wu JF, Jeng YM, Chen HL, Ni YH, Hsu HY, Chang MH. Quantification of Serum Matrix Metallopeptide 7 Levels May Assist in the Diagnosis and Predict the Outcome for Patients with Biliary Atresia. J Pediatr 2019; 208:30-37.e1. [PMID: 30853207 DOI: 10.1016/j.jpeds.2018.12.006] [Citation(s) in RCA: 57] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/24/2018] [Revised: 11/09/2018] [Accepted: 12/04/2018] [Indexed: 12/12/2022]
Abstract
OBJECTIVE To assess the diagnostic and prognostic usefulness of the serum matrix metallopeptidase-7 (MMP-7) level for biliary atresia in infants with cholestasis after hepatoportoenterostomy. STUDY DESIGN We enrolled 100 infants with cholestasis (age, 43.56 ± 1.97 days; 62 males) with a direct bilirubin level of >1 mg/dL, of whom 36 (36%) were diagnosed with biliary atresisa. The MMP-7 levels in serum samples collected during the cholestasis workup and 6 months after hepatoportoenterostomy were assessed by enzyme-linked immunosorbent assay. We quantified liver fibrosis by Picro Sirius red staining of collagen in specimens from the 81 infants with cholestasis. RESULTS Infants with biliary atresisa had a significantly higher serum MMP-7 level than that of non-biliary atresisa infants with cholestasis of equivalent age (P < .0001). Receiver operating characteristic analysis showed that a serum MMP-7 level of >1.43 ng/mL was predictive of biliary atresisa in infants with cholestasis (diagnostic accuracy, 88%). There was a positive correlation between the serum MMP-7 level and the severity of liver fibrosis (P = .0002). Survival analysis showed that the frequency of liver transplantation was significantly higher in infants with biliary atresisa with a serum MMP-7 level of >10.30 ng/mL compared with a serum MMP-7 level of ≤10.30 ng/mL after hepatoportoenterostomy (hazard ratio, 4.22; P = .02). CONCLUSIONS The serum MMP-7 level, which reflects the severity of liver fibrosis and can be determined noninvasively, may facilitate the diagnosis of biliary atresisa among infants with cholestasis. Moreover, the serum MMP-7 level after hepatoportoenterostomy is associated with a need for liver transplantation in infants with biliary atresisa.
Collapse
Affiliation(s)
- Jia-Feng Wu
- Department of Pediatrics, National Taiwan University Hospital, Taipei, Taiwan
| | - Yung-Ming Jeng
- Department of Pathology, National Taiwan University Hospital, Taipei, Taiwan
| | - Huey-Ling Chen
- Department of Pediatrics, National Taiwan University Hospital, Taipei, Taiwan; Department of Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan
| | - Yen-Hsuan Ni
- Department of Pediatrics, National Taiwan University Hospital, Taipei, Taiwan; Department of Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan
| | - Hong-Yuan Hsu
- Department of Pediatrics, National Taiwan University Hospital, Taipei, Taiwan
| | - Mei-Hwei Chang
- Department of Pediatrics, National Taiwan University Hospital, Taipei, Taiwan; Department of Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan.
| |
Collapse
|
|
45
|
Yang Z, Kusumanchi P, Ross RA, Heathers L, Chandler K, Oshodi A, Thoudam T, Li F, Wang L, Liangpunsakul S. Serum Metabolomic Profiling Identifies Key Metabolic Signatures Associated With Pathogenesis of Alcoholic Liver Disease in Humans. Hepatol Commun 2019; 3:542-557. [PMID: 30976744 PMCID: PMC6442705 DOI: 10.1002/hep4.1322] [Citation(s) in RCA: 53] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/20/2018] [Accepted: 01/11/2019] [Indexed: 12/17/2022] Open
Abstract
Alcoholic liver disease (ALD) develops in a subset of heavy drinkers (HDs). The goals of our study were to (1) characterize the global serum metabolomic changes in well-characterized cohorts of controls (Cs), HDs, and those with alcoholic cirrhosis (AC); (2) identify metabolomic signatures as potential diagnostic markers, and (3) determine the trajectory of serum metabolites in response to alcohol abstinence. Serum metabolic profiling was performed in 22 Cs, 147 HDs, and 33 patients with AC using ultraperformance liquid chromatography-tandem mass spectrometry. Hepatic gene expression was conducted in Cs (n = 16) and those with AC (n = 32). We found progressive changes in the quantities of metabolites from heavy drinking to AC. Taurine-conjugated bile acids (taurocholic acid [TCA], 127-fold; taurochenodeoxycholic acid [TCDCA], 131-fold; and tauroursodeoxycholic acid, 56-fold) showed more striking elevations than glycine-conjugated forms (glycocholic acid [GCA], 22-fold; glycochenodeoxycholic acid [GCDCA], 22-fold; and glycoursodeoxycholic acid [GUDCA], 11-fold). This was associated with increased liver cytochrome P450, family 7, subfamily B, member 1 and taurine content (more substrates); the latter was due to dysregulation of homocysteine metabolism. Increased levels of GCDCA, TCDCA, GCA, and TCA positively correlated with disease progression from Child-Pugh A to C and Model for End-Stage Liver Disease scores, whereas GCDCA, GCA, and GUDCA were better predictors of alcohol abstinence. The levels of glucagon-like peptide 1 (GLP-1) and fibroblast growth factor (FGF) 21 but not FGF19 were increased in HDs, and all three were further increased in those with AC. Conclusion: Serum taurine/glycine-conjugated bile acids could serve as noninvasive markers to predict the severity of AC, whereas GLP-1 and FGF21 may indicate a progression from heavy drinking to AC.
Collapse
Affiliation(s)
- Zhihong Yang
- Division of Gastroenterology and Hepatology, Department of MedicineIndiana University School of MedicineIndianapolisIN
| | - Praveen Kusumanchi
- Division of Gastroenterology and Hepatology, Department of MedicineIndiana University School of MedicineIndianapolisIN
| | - Ruth A. Ross
- Division of Gastroenterology and Hepatology, Department of MedicineIndiana University School of MedicineIndianapolisIN
| | - Laura Heathers
- Division of Gastroenterology and Hepatology, Department of MedicineIndiana University School of MedicineIndianapolisIN
- Department of Medical and Molecular GeneticsIndiana University School of MedicineIndianapolisIN
| | - Kristina Chandler
- Division of Gastroenterology and Hepatology, Department of MedicineIndiana University School of MedicineIndianapolisIN
| | - Adepeju Oshodi
- Division of Gastroenterology and Hepatology, Department of MedicineIndiana University School of MedicineIndianapolisIN
| | - Themis Thoudam
- Division of Gastroenterology and Hepatology, Department of MedicineIndiana University School of MedicineIndianapolisIN
- Department of Biomedical ScienceKyungpook National UniversityDaeguSouth Korea
| | - Feng Li
- Department of Molecular and Cellular BiologyBaylor College of MedicineHoustonTX
| | - Li Wang
- Department of Physiology and Neurobiology and the Institute for Systems GenomicsUniversity of ConnecticutStorrsCT
- Veterans Affairs Connecticut Healthcare SystemWest HavenCT
- Department of Internal Medicine, Liver CenterYale UniversityNew HavenCT
| | - Suthat Liangpunsakul
- Division of Gastroenterology and Hepatology, Department of MedicineIndiana University School of MedicineIndianapolisIN
- Department of Biochemistry and Molecular BiologyIndiana University School of MedicineIndianapolisIN
- Roudebush Veterans Administration Medical CenterIndianapolisIN
| |
Collapse
|
|
46
|
Zhang Y, Lu Y, Ji H, Li Y. Anti-inflammatory, anti-oxidative stress and novel therapeutic targets for cholestatic liver injury. Biosci Trends 2019; 13:23-31. [PMID: 30814402 DOI: 10.5582/bst.2018.01247] [Citation(s) in RCA: 37] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
Cholestasis is a pathological process in which bile drainage is poor for a variety of reasons. Many studies have shown that cholestatic liver injury is a neutrophil-mediated inflammatory response, and oxidative stress induced by neutrophils is the main mechanism of liver cell death. The literature summarizes the bile acid signaling pathway, the neutrophil chemotaxis recruitment process during cholestasis, and the oxidative stress damage produced by neutrophil activation, summarizes the latest research progress. Sphingosine-1-phosphate receptor (S1PR) is a potential therapeutic target for cholestasis that reduces neutrophil aggregation without inhibiting systemic immune status. Early growth response factor 1 (Egr-1) may play a central role in the inflammation induced by cholestasis, and it is also a potential therapeutic target to inhibit the inflammation induced by cholestasis. Strengthening the antioxidant system of hepatocytes to cope with oxidative stress of neutrophils is a feasible treatment for cholestatic liver injury.
Collapse
Affiliation(s)
- Yafei Zhang
- Department of General Surgery, Second Affiliated Hospital of Xi'an Jiaotong University
| | - Yuxuan Lu
- The High School Affiliated to xi'an Jiaotong University
| | - Hong Ji
- Department of General Surgery, Second Affiliated Hospital of Xi'an Jiaotong University
| | - Yiming Li
- Department of General Surgery, Second Affiliated Hospital of Xi'an Jiaotong University
| |
Collapse
|
|
47
|
H19 potentiates let-7 family expression through reducing PTBP1 binding to their precursors in cholestasis. Cell Death Dis 2019; 10:168. [PMID: 30778047 PMCID: PMC6379488 DOI: 10.1038/s41419-019-1423-6] [Citation(s) in RCA: 34] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2018] [Revised: 12/27/2018] [Accepted: 01/21/2019] [Indexed: 12/22/2022]
Abstract
Cholestasis induces the hepatic long non-coding RNA H19, which promotes the progression of cholestatic liver fibrosis. However, microRNAs that are dysregulated by H19 during cholestasis remain elusive. Using miRNA-sequencing analysis followed by qPCR validation, we identified marked upregulation of eight members of the let-7 family in cholestatic livers by bile duct ligation (BDL) and H19 overexpression. In particular, the expression of let-7a-1/7d/7f-1 was highly induced in H19-BDL livers but decreased in H19KO-BDL livers. Interestingly, H19 decreased the nuclear let-7 precursors as well as the primary transcripts of let-7a-1/7d/7f-1 levels in BDL mouse livers. Bioinformatics, RNA pull-down, and RNA immunoprecipitation (RIP) assays revealed that the crucial RNA-binding protein polypyrimidine tract-binding protein 1 (PTBP1), an H19 interaction partner, interacted with the precursors of let-7a-1 and let-7d and suppressed their maturation. Both PTBP1 and let-7 expression was differentially regulated by different bile acid species in hepatocyte and cholangiocyte cells. Further, H19 negatively regulated PTBP1's mRNA and protein levels but did not affect its subcellular distribution in BDL mouse livers. Moreover, we found that H19 restrained but PTBP1 facilitated the bioavailability of let-7 miRNAs to their targets. Taken together, this study revealed for the first time that H19 promoted let-7 expression by decreasing PTBP1's expression level and its binding to the let-7 precursors in cholestasis.
Collapse
|
|
48
|
Li Yim AYF, de Bruyn JR, Duijvis NW, Sharp C, Ferrero E, de Jonge WJ, Wildenberg ME, Mannens MMAM, Buskens CJ, D’Haens GR, Henneman P, te Velde AA. A distinct epigenetic profile distinguishes stenotic from non-inflamed fibroblasts in the ileal mucosa of Crohn's disease patients. PLoS One 2018; 13:e0209656. [PMID: 30589872 PMCID: PMC6307755 DOI: 10.1371/journal.pone.0209656] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2018] [Accepted: 12/10/2018] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND The chronic remitting and relapsing intestinal inflammation characteristic of Crohn's disease frequently leads to fibrosis and subsequent stenosis of the inflamed region. Approximately a third of all Crohn's disease patients require resection at some stage in their disease course. As the pathogenesis of Crohn's disease associated fibrosis is largely unknown, a strong necessity exists to better understand the pathophysiology thereof. METHODS In this study, we investigated changes of the DNA methylome and transcriptome of ileum-derived fibroblasts associated to the occurrence of Crohn's disease associated fibrosis. Eighteen samples were included in a DNA methylation array and twenty-one samples were used for RNA sequencing. RESULTS Most differentially methylated regions and differentially expressed genes were observed when comparing stenotic with non-inflamed samples. By contrast, few differences were observed when comparing Crohn's disease with non-Crohn's disease, or inflamed with non-inflamed tissue. Integrative methylation and gene expression analyses revealed dysregulation of genes associated to the PRKACA and E2F1 network, which is involved in cell cycle progression, angiogenesis, epithelial to mesenchymal transition, and bile metabolism. CONCLUSION Our research provides evidence that the methylome and the transcriptome are systematically dysregulated in stenosis-associated fibroblasts.
Collapse
Affiliation(s)
- Andrew Y. F. Li Yim
- Genome Diagnostics Laboratory, Department of Clinical Genetics, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands
- Epigenetics Discovery Performance Unit, GlaxoSmithKline, Stevenage, United Kingdom
| | - Jessica R. de Bruyn
- Tytgat Institute for Liver and Intestinal Research, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands
- Department of Gastroenterology, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands
| | - Nicolette W. Duijvis
- Tytgat Institute for Liver and Intestinal Research, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands
| | - Catriona Sharp
- Epigenetics Discovery Performance Unit, GlaxoSmithKline, Stevenage, United Kingdom
| | - Enrico Ferrero
- Computational Biology, Target Sciences, GlaxoSmithKline, Stevenage, United Kingdom
| | - Wouter J. de Jonge
- Tytgat Institute for Liver and Intestinal Research, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands
| | - Manon E. Wildenberg
- Tytgat Institute for Liver and Intestinal Research, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands
| | - Marcel M. A. M. Mannens
- Genome Diagnostics Laboratory, Department of Clinical Genetics, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands
| | - Christianne J. Buskens
- Department of Surgery, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands
| | - Geert R. D’Haens
- Department of Gastroenterology, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands
| | - Peter Henneman
- Genome Diagnostics Laboratory, Department of Clinical Genetics, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands
| | - Anje A. te Velde
- Tytgat Institute for Liver and Intestinal Research, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands
- * E-mail:
| |
Collapse
|
|
49
|
Souza T, Trairatphisan P, Piñero J, Furlong LI, Saez-Rodriguez J, Kleinjans J, Jennen D. Embracing the Dark Side: Computational Approaches to Unveil the Functionality of Genes Lacking Biological Annotation in Drug-Induced Liver Injury. Front Genet 2018; 9:527. [PMID: 30515189 PMCID: PMC6255978 DOI: 10.3389/fgene.2018.00527] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2018] [Accepted: 10/19/2018] [Indexed: 12/03/2022] Open
Abstract
In toxicogenomics, functional annotation is an important step to gain additional insights into genes with aberrant expression that drive pathophysiological mechanisms. Nevertheless, there exists a gap on annotation of these genes which often hampers the interpretation of results and limits their applicability in translational medicine. In this study, we evaluated the coverage of functional annotations of differentially expressed genes (DEGs) induced by 10 selected compounds from the TG-GATEs database identified as high- or no-risk in causing drug-induced liver injury (most-DILI or no-DILI, respectively) using in vitro human data. Functional roles of DEGs not present in the most common biological annotation databases – termed “dark genes” – were unveiled via literature mining and via the identification of shared regulatory transcription factors or signaling pathways. Our results demonstrated that there were approximately 13% of dark genes induced by these compounds in vitro and we were able to obtain additional relevant information for up to 76% of those. Using interactome data from several sources, we have uncovered genes such as LRBA, and WDR26 as highly connected in the protein network that play roles in drug response. Genes such as MALAT1, H19, and MIR29C – whose links to hepatotoxicity have been confirmed – were identified as markers for the most-DILI group and appeared as top hits across all literature-based mining methods. Furthermore, we investigated the potential impact of dark genes on liver toxicity by identifying their rat orthologs in combination with their correlation to drug-induced liver pathologies observed in vivo following chemical exposure. We identified a set of important regulatory transcription factors of dark genes for all most-DILI compounds including E2F1 and JUND with supporting evidences in literature and we found Magee1 correlated with chemically induced bile duct hyperplasia and adverse responses at 29 days in rats in vivo. In conclusion, in this study we show the potential role of these poorly annotated genes in mechanisms underlying hepatotoxicity and offer a number of computational approaches that may help to minimize current gaps in gene annotation and highlight their values as potential biomarkers in toxicological studies.
Collapse
Affiliation(s)
- Terezinha Souza
- Department of Toxicogenomics, GROW School for Oncology and Developmental Biology, Maastricht University, Maastricht, Netherlands
| | - Panuwat Trairatphisan
- Joint Research Center for Computational Biomedicine (JRC-COMBINE), Faculty of Medicine, RWTH Aachen University, Aachen, Germany
| | - Janet Piñero
- Integrative Biomedical Informatics Group, Research Programme on Biomedical Informatics (GRIB), Department of Experimental and Health Sciences (DCEXS), Hospital del Mar Medical Research Institute (IMIM), Universitat Pompeu Fabra, Barcelona, Spain
| | - Laura I Furlong
- Integrative Biomedical Informatics Group, Research Programme on Biomedical Informatics (GRIB), Department of Experimental and Health Sciences (DCEXS), Hospital del Mar Medical Research Institute (IMIM), Universitat Pompeu Fabra, Barcelona, Spain
| | - Julio Saez-Rodriguez
- Joint Research Center for Computational Biomedicine (JRC-COMBINE), Faculty of Medicine, RWTH Aachen University, Aachen, Germany.,European Bioinformatics Institute, European Molecular Biology Laboratory (EMBL-EBI), Cambridge, United Kingdom
| | - Jos Kleinjans
- Department of Toxicogenomics, GROW School for Oncology and Developmental Biology, Maastricht University, Maastricht, Netherlands
| | - Danyel Jennen
- Department of Toxicogenomics, GROW School for Oncology and Developmental Biology, Maastricht University, Maastricht, Netherlands
| |
Collapse
|
|
50
|
Ye Y, Gu B, Wang Y, Shen S, Huang W. E2F1‐mediated MNX1‐AS1‐miR‐218‐5p‐SEC61A1 feedback loop contributes to the progression of colon adenocarcinoma. J Cell Biochem 2018; 120:6145-6153. [PMID: 30362161 DOI: 10.1002/jcb.27902] [Citation(s) in RCA: 38] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2018] [Accepted: 09/24/2018] [Indexed: 01/01/2023]
Affiliation(s)
- Yaqun Ye
- The Operating Room The First Affiliated Hospital of Wenzhou Medical University Wenzhou China
| | - Binbin Gu
- Nutrition Department The First Affiliated Hospital of Wenzhou Medical University Wenzhou China
| | - Yi Wang
- Nutrition Department The First Affiliated Hospital of Wenzhou Medical University Wenzhou China
| | - Sudan Shen
- Nutrition Department The First Affiliated Hospital of Wenzhou Medical University Wenzhou China
| | - Wei Huang
- Nutrition Department The First Affiliated Hospital of Wenzhou Medical University Wenzhou China
| |
Collapse
|