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Carbone F, Després JP, Ioannidis JPA, Neeland IJ, Garruti G, Busetto L, Liberale L, Ministrini S, Vilahur G, Schindler TH, Macedo MP, Di Ciaula A, Krawczyk M, Geier A, Baffy G, Faienza MF, Farella I, Santoro N, Frühbeck G, Yárnoz-Esquiroz P, Gómez-Ambrosi J, Chávez-Manzanera E, Vázquez-Velázquez V, Oppert JM, Kiortsis DN, Sbraccia P, Zoccali C, Portincasa P, Montecucco F. Bridging the gap in obesity research: A consensus statement from the European Society for Clinical Investigation. Eur J Clin Invest 2025:e70059. [PMID: 40371883 DOI: 10.1111/eci.70059] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/09/2025] [Accepted: 04/12/2025] [Indexed: 05/16/2025]
Abstract
BACKGROUND Most forms of obesity are associated with chronic diseases that remain a global public health challenge. AIMS Despite significant advancements in understanding its pathophysiology, effective management of obesity is hindered by the persistence of knowledge gaps in epidemiology, phenotypic heterogeneity and policy implementation. MATERIALS AND METHODS This consensus statement by the European Society for Clinical Investigation identifies eight critical areas requiring urgent attention. Key gaps include insufficient long-term data on obesity trends, the inadequacy of body mass index (BMI) as a sole diagnostic measure, and insufficient recognition of phenotypic diversity in obesity-related cardiometabolic risks. Moreover, the socio-economic drivers of obesity and its transition across phenotypes remain poorly understood. RESULTS The syndemic nature of obesity, exacerbated by globalization and environmental changes, necessitates a holistic approach integrating global frameworks and community-level interventions. This statement advocates for leveraging emerging technologies, such as artificial intelligence, to refine predictive models and address phenotypic variability. It underscores the importance of collaborative efforts among scientists, policymakers, and stakeholders to create tailored interventions and enduring policies. DISCUSSION The consensus highlights the need for harmonizing anthropometric and biochemical markers, fostering inclusive public health narratives and combating stigma associated with obesity. By addressing these gaps, this initiative aims to advance research, improve prevention strategies and optimize care delivery for people living with obesity. CONCLUSION This collaborative effort marks a decisive step towards mitigating the obesity epidemic and its profound impact on global health systems. Ultimately, obesity should be considered as being largely the consequence of a socio-economic model not compatible with optimal human health.
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Affiliation(s)
- Federico Carbone
- Department of Internal Medicine, University of Genoa, Genoa, Italy
- IRCCS Ospedale Policlinico San Martino, Genoa, Genoa, Italy
| | - Jean-Pierre Després
- Institut Universitaire de Cardiologie et de Pneumologie de Québec - Université Laval, Québec, Québec, Canada
- VITAM - Centre de Recherche en santé Durable, Centre intégré Universitaire de santé et de Services Sociaux de la Capitale-Nationale, Québec, Québec, Canada
| | - John P A Ioannidis
- Department of Medicine, Stanford Cardiovascular Institute, and Meta-Research Innovation Center at Stanford (METRICS), Stanford University, Stanford, California, USA
- Department of Epidemiology and Population Health, Stanford Cardiovascular Institute, and Meta-Research Innovation Center at Stanford (METRICS), Stanford University, Stanford, California, USA
- Department of Biomedical Science, Stanford Cardiovascular Institute, and Meta-Research Innovation Center at Stanford (METRICS), Stanford University, Stanford, California, USA
| | - Ian J Neeland
- Case Western Reserve University School of Medicine, Cleveland, Ohio, USA
- Department of Cardiovascular Disease, Harrington Heart and Vascular Institute, Cleveland, Ohio, USA
| | - Gabriella Garruti
- Department of Precision and Regenerative Medicine and Ionian Area (DiMePre-J), University of Bari "Aldo Moro", Bari, Italy
| | - Luca Busetto
- Department of Medicine, University of Padua, Padua, Italy
| | - Luca Liberale
- Department of Internal Medicine, University of Genoa, Genoa, Italy
- IRCCS Ospedale Policlinico San Martino, Genoa, Genoa, Italy
| | - Stefano Ministrini
- Center for Molecular Cardiology, University of Zurich, Schlieren, Switzerland
- Cardiology Department, Luzerner Kantonspital, Lucerne, Switzerland
| | - Gemma Vilahur
- Research Institute, Hospital de la Santa Creu i Sant Pau, IIB-Sant Pau, IIB-Sant Pau, Barcelona, Spain
- CiberCV, Institute Carlos III, Madrid, Spain
| | - Thomas H Schindler
- Washington University in St. Louis, Mallinckrodt Institute of Radiology, Division of Nuclear Medicine, Cardiovascular Medicine, Washington University School of Medicine, St. Louis, Missouri, USA
| | - Maria Paula Macedo
- APDP - Diabetes Portugal, Education and Research Center, Lisbon, Portugal
- iNOVA4Health, NOVA Medical School | Faculdade de Ciências Médicas, NMS | FCM, Universidade Nova de Lisboa, Lisbon, Portugal
| | - Agostino Di Ciaula
- Department of Precision and Regenerative Medicine and Ionian Area (DiMePre-J), University of Bari "Aldo Moro", Bari, Italy
| | - Marcin Krawczyk
- Department of Gastroenterology, Hepatology and Transplant Medicine, Medical Faculty, University of Duisburg-Essen, Essen, Germany
- Laboratory of Metabolic Liver Diseases, Department of General, Transplant and Liver Surgery, Centre for Preclinical Research, Medical University of Warsaw, Warsaw, Poland
| | - Andreas Geier
- Interdisciplinary Amyloidosis Center of Northern Bavaria, University Hospital of Würzburg, Würzburg, Germany
- Department of Internal Medicine II, Hepatology, University Hospital of Würzburg, Würzburg, Germany
| | - Gyorgy Baffy
- Department of Medicine, VA Boston Healthcare System, Harvard Medical School, Boston, Massachusetts, USA
| | - Maria Felicia Faienza
- Department of Precision and Regenerative Medicine and Ionian Area (DiMePre-J), University of Bari "Aldo Moro", Bari, Italy
| | - Ilaria Farella
- Department of Medicine and Surgery, LUM University, Casamassima, Italy
| | - Nicola Santoro
- Department of Pediatrics, Yale University School of Medicine, New Haven, Connecticut, USA
- Department of Medicine and Health Sciences, "V. Tiberio" University of Molise, Campobasso, Italy
| | - Gema Frühbeck
- Department of Endocrinology and Nutrition, Cancer Center Clínica Universidad de Navarra (CCUN), Pamplona, Spain
- IdiSNA (Instituto de Investigación en la Salud de Navarra), Pamplona, Spain
- CIBERObn (CIBER Fisiopatología de la Obesidad y Nutrición), Instituto de Salud Carlos III, Madrid, Spain
| | - Patricia Yárnoz-Esquiroz
- Department of Endocrinology and Nutrition, Cancer Center Clínica Universidad de Navarra (CCUN), Pamplona, Spain
- IdiSNA (Instituto de Investigación en la Salud de Navarra), Pamplona, Spain
- CIBERObn (CIBER Fisiopatología de la Obesidad y Nutrición), Instituto de Salud Carlos III, Madrid, Spain
| | - Javier Gómez-Ambrosi
- Department of Endocrinology and Nutrition, Cancer Center Clínica Universidad de Navarra (CCUN), Pamplona, Spain
- IdiSNA (Instituto de Investigación en la Salud de Navarra), Pamplona, Spain
- CIBERObn (CIBER Fisiopatología de la Obesidad y Nutrición), Instituto de Salud Carlos III, Madrid, Spain
| | - Emma Chávez-Manzanera
- Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
| | | | - Jean-Michel Oppert
- Department of Nutrition, Pitié-Salpêtrière Hospital (AP-HP), Human Nutrition Research Center Ile-de-France (CRNH IdF), Sorbonne University, Paris, France
| | - Dimitrios N Kiortsis
- Atherothrombosis Research Centre, Faculty of Medicine, University of Ioannina, Ioannina, Greece
| | - Paolo Sbraccia
- Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy
| | - Carmine Zoccali
- Renal Research Institute, New York, New York, USA
- Institute of Molecular Biology and Genetics (Biogem), Ariano Irpino, Italy
- Associazione Ipertensione Nefrologia Trapianto Renale (IPNET), c/o Nefrologia, Grande Ospedale Metropolitano, Reggio Calabria, Italy
| | - Piero Portincasa
- Department of Precision and Regenerative Medicine and Ionian Area (DiMePre-J), University of Bari "Aldo Moro", Bari, Italy
| | - Fabrizio Montecucco
- Department of Internal Medicine, University of Genoa, Genoa, Italy
- IRCCS Ospedale Policlinico San Martino, Genoa, Genoa, Italy
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Cai C, Luo H, Peng J, Zhen X, Shen X, Xi X, Zhu J, Fang Y, Chen X, Wang J, Yu C, Zhang P, Xu C. The deubiquitinase USP28 maintains the expression of PPARγ and its inactivation protects mice from diet-induced MASH and hepatocarcinoma. Mol Ther 2025; 33:1825-1841. [PMID: 39905730 PMCID: PMC11997470 DOI: 10.1016/j.ymthe.2025.01.046] [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: 08/05/2024] [Revised: 12/17/2024] [Accepted: 01/30/2025] [Indexed: 02/06/2025] Open
Abstract
Metabolic dysfunction-associated steatohepatitis (MASH), a progressive form of metabolic dysfunction-associated fatty liver disease (MAFLD), is a leading cause of liver disease worldwide and can progress to cirrhosis and cancer. Despite its prevalence, the pathogenesis of MASH remains poorly understood, and there is only one U.S. Food and Drug Administration-approved treatment, highlighting the need for new therapeutic strategies. Peroxisome proliferator-activated receptor (PPAR)γ is activated in the liver under high-fat or obese conditions, promoting lipid storage and contributing to MASH progression. We found that USP28 expression is elevated in the livers of MAFLD/MASH patients. Through dietary induction, including a methionine-choline deficient (MCD) diet and a western diet (WD) combined with carbon tetrachloride (CCl4) injections, we established two severe mouse models of MASH to explore the role of USP28. Mechanistically, the hepatic deubiquitinase (DUB) USP28 directly binds to PPARγ, preventing its ubiquitination and subsequent degradation, thereby maintaining the integrity of the PPARγ signaling pathway. In the absence of Usp28 or if the DUB is inhibited, PPARγ is downregulated, and the PPAR signaling pathway is inhibited, enhancing cellular defenses against excess fat. Both genetic and pharmacological inactivation of Usp28 significantly reduced MASH severity induced by the MCD diet or WD-CCl4 regimen, as well as WD-CCl4-induced hepatocellular carcinoma in mice.
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Affiliation(s)
- Changzhou Cai
- Department of Gastroenterology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China; Department of Gastroenterology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310016, China
| | - Hangqi Luo
- Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou 310058, China
| | - Jin Peng
- Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Xinghua Zhen
- Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou 310058, China
| | - Xiang Shen
- Chaser Therapeutics, Inc., Hangzhou, Zhejiang 310018, China
| | - Xiaomei Xi
- Chaser Therapeutics, Inc., Hangzhou, Zhejiang 310018, China
| | - Jianrong Zhu
- Chaser Therapeutics, Inc., Hangzhou, Zhejiang 310018, China
| | - Yanfei Fang
- Department of Gastroenterology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310016, China
| | - Xiaoli Chen
- Department of Gastroenterology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310016, China
| | - Jiewei Wang
- Department of Gastroenterology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Chaohui Yu
- Department of Gastroenterology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China.
| | - Pumin Zhang
- Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou 310058, China; Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China; Cancer Center, Zhejiang University, Hangzhou 310058, China.
| | - Chengfu Xu
- Department of Gastroenterology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China.
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Fang RR, Yang QF, Zhao J, Xu SZ. A Novel Signature Combing Cuproptosis- and Ferroptosis-Related Genes in Nonalcoholic Fatty Liver Disease. CHINESE MEDICAL SCIENCES JOURNAL = CHUNG-KUO I HSUEH K'O HSUEH TSA CHIH 2024; 39:261-272. [PMID: 39789929 DOI: 10.24920/004403] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/12/2025]
Abstract
OBJECTIVES To identify cuproptosis- and ferroptosis-related genes involved in nonalcoholic fatty liver disease and to determine the diagnostic value of hub genes. METHODS The gene expression dataset GSE89632 was retrieved from the Gene Expression Omnibus database to identify differentially expressed genes (DEGs) between the non-alcoholic steatohepatitis (NASH) group and the healthy group using the 'limma' package in R software and weighted gene co-expression network analysis. Gene ontology, kyoto encyclopedia of genes and genomes pathway, and single-sample gene set enrichment analyses were performed to identify functional enrichment of DEGs. Ferroptosis- and cuproptosis-related genes were obtained from the FerrDb V2 database and available literatures, respectively. A combined signature for cuproptosis- and ferroptosis-related genes, called CRF, was constructed using the STRING database. Hub genes were identified by overlapping DEGs, WGCNA-derived key genes, and combined signature CRF genes, and validated using the GSE109836 and GSE227714 datasets and real-time quantitative polymerase chain reaction. A nomogram of NASH diagnostic model was established utilizing the 'rms' package in R software based on the hub genes, and the diagnostic value of hub genes was assessed using receiver operating characteristic curve analysis. In addition, immune cell infiltration in NASH versus healthy controls was examined using the CIBERSORT algorithm. The relationships among various infiltrated immune cells were explored with Spearman's correlation analysis. RESULTS Analysis of GSE89632 identified 236 DEGs between the NASH group and the healthy group. WGCNA highlighted 8 significant modules and 11,095 pivotal genes, of which 330 genes constituted CRF. Intersection analysis identified IL6, IL1B, JUN, NR4A1, and PTGS2 as hub genes. The hub genes were all downregulated in the NASH group, and this result was further verified by the NASH validation dataset and real-time quantitative polymerase chain reaction. Receiver operating characteristic curve analysis confirmed the diagnostic efficacy of these hub genes with areas under the curve of 0.985, 0.941, 1.000, 0.967, and 0.985, respectively. Immune infiltration assessment revealed that gamma delta T cells, M1 macrophages, M2 macrophages, and resting mast cells were predominantly implicated. CONCLUSIONS Our investigation underscores the significant association of cuproptosis- and ferroptosis-related genes, specifically IL6, IL1B, JUN, NR4A1, and PTGS2, with NASH. These findings offer novel insights into the pathogenesis of NASH, potentially guiding future diagnostic and therapeutic strategies.
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Affiliation(s)
| | | | - Jing Zhao
- Shaanxi Key Laboratory of Acupuncture & Medicine, Shaanxi University of Chinese Medicine, Xianyang 712046, Shaanxi, China
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Sanal MG, Gish RG, Méndez-Sánchez N, Yu ML, Chan WK, Wei L, Grønbæk H, Zheng M, George J. NAFLD to MAFLD: collaboration, not confusion - rethinking the naming of fatty liver disease. METABOLISM AND TARGET ORGAN DAMAGE 2024; 4. [DOI: 10.20517/mtod.2024.54] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/06/2025]
Abstract
The recent shift from “non-alcoholic fatty liver disease” (NAFLD) and “metabolic associated fatty liver disease” (MAFLD) to “metabolic dysfunction-associated steatotic liver disease” (MASLD) has raised questions about its scientific basis and impact on patient understanding. This renaming may create confusion rather than clarity. A collaborative approach involving healthcare professionals, researchers, and patients to establish terminology that balances scientific accuracy with accessibility is needed. Effective disease naming should be accurate, unique, consistent, objective, and accessible - qualities essential for clear communication in healthcare. Disease name is more than scientific correctness because naming conventions for public use, especially anything related to health, must be a matter of convenience, ethics, and cultural and social acceptance. Education and straightforward communication should take precedence over renaming, helping patients and healthcare providers fully understand the complexities and implications of liver disease for treatment. After all, from a scientific and public health perspective, MAFLD has clear advantages over MASLD.
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Carli F, Della Pepa G, Sabatini S, Vidal Puig A, Gastaldelli A. Lipid metabolism in MASLD and MASH: From mechanism to the clinic. JHEP Rep 2024; 6:101185. [PMID: 39583092 PMCID: PMC11582433 DOI: 10.1016/j.jhepr.2024.101185] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/23/2024] [Revised: 07/29/2024] [Accepted: 08/01/2024] [Indexed: 11/26/2024] Open
Abstract
Metabolic dysfunction-associated steatotic liver disease/steatohepatitis (MASLD/MASH) is recognised as a metabolic disease characterised by excess intrahepatic lipid accumulation due to lipid overflow and synthesis, alongside impaired oxidation and/or export of these lipids. But where do these lipids come from? The main pathways related to hepatic lipid accumulation are de novo lipogenesis and excess fatty acid transport to the liver (due to increased lipolysis, adipose tissue insulin resistance, as well as excess dietary fatty acid intake, in particular of saturated fatty acids). Not only triglycerides but also other lipids are secreted by the liver and are associated with a worse histological profile in MASH, as shown by lipidomics. Herein, we review the role of lipid metabolism in MASLD/MASH and discuss the impact of weight loss (diet, bariatric surgery, GLP-1RAs) or other pharmacological treatments (PPAR or THRβ agonists) on hepatic lipid metabolism, lipidomics, and the resolution of MASH.
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Affiliation(s)
- Fabrizia Carli
- Cardiometabolic Risk Laboratory, Institute of Clinical Physiology (IFC), National Research Council (CNR), Pisa, Italy
| | - Giuseppe Della Pepa
- Cardiometabolic Risk Laboratory, Institute of Clinical Physiology (IFC), National Research Council (CNR), Pisa, Italy
| | - Silvia Sabatini
- Cardiometabolic Risk Laboratory, Institute of Clinical Physiology (IFC), National Research Council (CNR), Pisa, Italy
| | - Antonio Vidal Puig
- Metabolic Research Laboratories, Medical Research Council Institute of Metabolic Science University of Cambridge, Cambridge CB2 0QQ UK
- Centro de Investigacion Principe Felipe Valencia 46012 Spain
- Cambridge University Nanjing Centre of Technology and Innovation, Nanjing, China
| | - Amalia Gastaldelli
- Cardiometabolic Risk Laboratory, Institute of Clinical Physiology (IFC), National Research Council (CNR), Pisa, Italy
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Noh SG, Kim HW, Kim S, Chung KW, Jung YS, Yoon JH, Yu BP, Lee J, Chung HY. Senoinflammation as the underlying mechanism of aging and its modulation by calorie restriction. Ageing Res Rev 2024; 101:102503. [PMID: 39284417 DOI: 10.1016/j.arr.2024.102503] [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: 07/04/2024] [Revised: 08/25/2024] [Accepted: 09/09/2024] [Indexed: 09/22/2024]
Abstract
Senoinflammation is characterized by an unresolved low-grade inflammatory process that affects multiple organs and systemic functions. This review begins with a brief overview of the fundamental concepts and frameworks of senoinflammation. It is widely involved in the aging of various organs and ultimately leads to progressive systemic degeneration. Senoinflammation underlying age-related inflammation, is causally related to metabolic dysregulation and the formation of senescence-associated secretory phenotype (SASP) during aging and age-related diseases. This review discusses the biochemical evidence and molecular biology data supporting the concept of senoinflammation and its regulatory processes, highlighting the anti-aging and anti-inflammatory effects of calorie restriction (CR). Experimental data from CR studies demonstrated effective suppression of various pro-inflammatory cytokines and chemokines, lipid accumulation, and SASP during aging. In conclusion, senoinflammation represents the basic mechanism that creates a microenvironment conducive to aging and age-related diseases. Furthermore, it serves as a potential therapeutic target for mitigating aging and age-related diseases.
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Affiliation(s)
- Sang Gyun Noh
- Research Institute for Drug Development, Pusan National University, 2 Busandaehak-ro 63beon-gil, Geumjeong-gu, Busan 46241, Republic of Korea
| | - Hyun Woo Kim
- Research Institute for Drug Development, Pusan National University, 2 Busandaehak-ro 63beon-gil, Geumjeong-gu, Busan 46241, Republic of Korea
| | - Seungwoo Kim
- Department of Pharmacy, College of Pharmacy, Pusan National University, 2 Busandaehak-ro 63beon-gil, Geumjeong-gu, Busan 46241, Republic of Korea
| | - Ki Wung Chung
- Research Institute for Drug Development, Pusan National University, 2 Busandaehak-ro 63beon-gil, Geumjeong-gu, Busan 46241, Republic of Korea; Department of Pharmacy, College of Pharmacy, Pusan National University, 2 Busandaehak-ro 63beon-gil, Geumjeong-gu, Busan 46241, Republic of Korea
| | - Young-Suk Jung
- Research Institute for Drug Development, Pusan National University, 2 Busandaehak-ro 63beon-gil, Geumjeong-gu, Busan 46241, Republic of Korea; Department of Pharmacy, College of Pharmacy, Pusan National University, 2 Busandaehak-ro 63beon-gil, Geumjeong-gu, Busan 46241, Republic of Korea
| | - Jeong-Hyun Yoon
- Research Institute for Drug Development, Pusan National University, 2 Busandaehak-ro 63beon-gil, Geumjeong-gu, Busan 46241, Republic of Korea; Department of Pharmacy, College of Pharmacy, Pusan National University, 2 Busandaehak-ro 63beon-gil, Geumjeong-gu, Busan 46241, Republic of Korea
| | - Byung Pal Yu
- Department of Physiology, The University of Texas Health Science Center at San Antonio, San Antonio, TX, USA
| | - Jaewon Lee
- Research Institute for Drug Development, Pusan National University, 2 Busandaehak-ro 63beon-gil, Geumjeong-gu, Busan 46241, Republic of Korea; Department of Pharmacy, College of Pharmacy, Pusan National University, 2 Busandaehak-ro 63beon-gil, Geumjeong-gu, Busan 46241, Republic of Korea.
| | - Hae Young Chung
- Research Institute for Drug Development, Pusan National University, 2 Busandaehak-ro 63beon-gil, Geumjeong-gu, Busan 46241, Republic of Korea; Department of Pharmacy, College of Pharmacy, Pusan National University, 2 Busandaehak-ro 63beon-gil, Geumjeong-gu, Busan 46241, Republic of Korea.
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Li X, Li M. Unlocking Cholesterol Metabolism in Metabolic-Associated Steatotic Liver Disease: Molecular Targets and Natural Product Interventions. Pharmaceuticals (Basel) 2024; 17:1073. [PMID: 39204178 PMCID: PMC11358954 DOI: 10.3390/ph17081073] [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: 07/07/2024] [Revised: 08/08/2024] [Accepted: 08/14/2024] [Indexed: 09/03/2024] Open
Abstract
Metabolic-associated steatotic liver disease (MASLD), the hepatic manifestation of metabolic syndrome, represents a growing global health concern. The intricate pathogenesis of MASLD, driven by genetic, metabolic, epigenetic, and environmental factors, leads to considerable clinical variability. Dysregulation of hepatic lipid metabolism, particularly cholesterol homeostasis, is a critical factor in the progression of MASLD and its more severe form, metabolic dysfunction-associated steatohepatitis (MASH). This review elucidates the multifaceted roles of cholesterol metabolism in MASLD, focusing on its absorption, transportation, biosynthesis, efflux, and conversion. We highlight recent advancements in understanding these processes and explore the therapeutic potential of natural products such as curcumin, berberine, and resveratrol in modulating cholesterol metabolism. By targeting key molecular pathways, these natural products offer promising strategies for MASLD management. Finally, this review also covers the clinical studies of natural products in MASLD, providing new insights for future research and clinical applications.
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Affiliation(s)
| | - Meng Li
- Institute of Digestive Diseases, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China;
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Ramalingam PS, Elangovan S, Mekala JR, Arumugam S. Liver X Receptors (LXRs) in cancer-an Eagle's view on molecular insights and therapeutic opportunities. Front Cell Dev Biol 2024; 12:1386102. [PMID: 38550382 PMCID: PMC10972936 DOI: 10.3389/fcell.2024.1386102] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2024] [Accepted: 03/04/2024] [Indexed: 01/03/2025] Open
Abstract
Cancer has become a serious health burden that results in high incidence and mortality rates every year, mainly due to various molecular alterations inside the cell. Liver X receptors (LXRs) dysregulation is one among them that plays a vital role in cholesterol metabolism, lipid metabolism and inflammation and also plays a crucial role in various diseases such as obesity, metabolic dysfunction-associated fatty liver disease (MAFLD), cardiovascular diseases, Type 2 diabetes, osteoporosis, and cancer. Studies report that the activation of LXRs inhibits cancer growth by inhibiting cellular proliferation, inducing apoptosis and autophagy, regulating cholesterol metabolism, various signalling pathways such as Wnt, and PI3K/AKT, modulating the expression levels of cell-cycle regulators, and promoting antitumor immunity inside the tumor microenvironment. In this review, we have discussed the role, structure, and functions of LXRs and also summarized their ligands along with their mechanism of action. In addition, the role of LXRs in various cancers, tumor immunity and tumor microenvironment (TME) along with the importance of precision medicine in LXR-targeted therapies has been discussed to emphasize the LXRs as potent targets for the development of novel cancer therapeutics.
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Affiliation(s)
| | - Sujatha Elangovan
- Protein Engineering Lab, School of Biosciences and Technology, Vellore Institute of Technology, Vellore, India
| | - Janaki Ramaiah Mekala
- Department of Biotechnology, Koneru Lakshmaiah Education Foundation (KLEF), Guntur, Andhra Pradesh, India
| | - Sivakumar Arumugam
- Protein Engineering Lab, School of Biosciences and Technology, Vellore Institute of Technology, Vellore, India
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Li Z, Zheng D, Zhang T, Ruan S, Li N, Yu Y, Peng Y, Wang D. The roles of nuclear receptors in cholesterol metabolism and reverse cholesterol transport in nonalcoholic fatty liver disease. Hepatol Commun 2024; 8:e0343. [PMID: 38099854 PMCID: PMC10727660 DOI: 10.1097/hc9.0000000000000343] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/24/2023] [Accepted: 10/28/2023] [Indexed: 12/18/2023] Open
Abstract
As the most prevalent chronic liver disease globally, NAFLD encompasses a pathological process that ranges from simple steatosis to NASH, fibrosis, cirrhosis, and HCC, closely associated with numerous extrahepatic diseases. While the initial etiology was believed to be hepatocyte injury caused by lipid toxicity from accumulated triglycerides, recent studies suggest that an imbalance of cholesterol homeostasis is of greater significance. The role of nuclear receptors in regulating liver cholesterol homeostasis has been demonstrated to be crucial. This review summarizes the roles and regulatory mechanisms of nuclear receptors in the 3 main aspects of cholesterol production, excretion, and storage in the liver, as well as their cross talk in reverse cholesterol transport. It is hoped that this review will offer new insights and theoretical foundations for the study of the pathogenesis and progression of NAFLD and provide new research directions for extrahepatic diseases associated with NAFLD.
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Han N, Yuan M, Yan L, Tang H. Emerging Insights into Liver X Receptor α in the Tumorigenesis and Therapeutics of Human Cancers. Biomolecules 2023; 13:1184. [PMID: 37627249 PMCID: PMC10452869 DOI: 10.3390/biom13081184] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2023] [Revised: 07/24/2023] [Accepted: 07/26/2023] [Indexed: 08/27/2023] Open
Abstract
Liver X receptor α (LXRα), a member of the nuclear receptor superfamily, is identified as a protein activated by ligands that interacts with the promoters of specific genes. It regulates cholesterol, bile acid, and lipid metabolism in normal physiological processes, and it participates in the development of some related diseases. However, many studies have demonstrated that LXRα is also involved in regulating numerous human malignancies. Aberrant LXRα expression is emerging as a fundamental and pivotal factor in cancer cell proliferation, invasion, apoptosis, and metastasis. Herein, we outline the expression levels of LXRα between tumor tissues and normal tissues via the Oncomine and Tumor Immune Estimation Resource (TIMER) 2.0 databases; summarize emerging insights into the roles of LXRα in the development, progression, and treatment of different human cancers and their diversified mechanisms; and highlight that LXRα can be a biomarker and therapeutic target in diverse cancers.
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Affiliation(s)
- Ning Han
- Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu 610041, China
- Division of Infectious Diseases, State Key Laboratory of Biotherapy, Sichuan University, Chengdu 610041, China
| | - Man Yuan
- Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu 610041, China
| | - Libo Yan
- Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu 610041, China
- Division of Infectious Diseases, State Key Laboratory of Biotherapy, Sichuan University, Chengdu 610041, China
| | - Hong Tang
- Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu 610041, China
- Division of Infectious Diseases, State Key Laboratory of Biotherapy, Sichuan University, Chengdu 610041, China
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11
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Zaiou M. Peroxisome Proliferator-Activated Receptor-γ as a Target and Regulator of Epigenetic Mechanisms in Nonalcoholic Fatty Liver Disease. Cells 2023; 12:1205. [PMID: 37190114 PMCID: PMC10136748 DOI: 10.3390/cells12081205] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2023] [Revised: 04/17/2023] [Accepted: 04/19/2023] [Indexed: 05/17/2023] Open
Abstract
Peroxisome proliferator-activated receptor-γ (PPARγ) belongs to the superfamily of nuclear receptors that control the transcription of multiple genes. Although it is found in many cells and tissues, PPARγ is mostly expressed in the liver and adipose tissue. Preclinical and clinical studies show that PPARγ targets several genes implicated in various forms of chronic liver disease, including nonalcoholic fatty liver disease (NAFLD). Clinical trials are currently underway to investigate the beneficial effects of PPARγ agonists on NAFLD/nonalcoholic steatohepatitis. Understanding PPARγ regulators may therefore aid in unraveling the mechanisms governing the development and progression of NAFLD. Recent advances in high-throughput biology and genome sequencing have greatly facilitated the identification of epigenetic modifiers, including DNA methylation, histone modifiers, and non-coding RNAs as key factors that regulate PPARγ in NAFLD. In contrast, little is still known about the particular molecular mechanisms underlying the intricate relationships between these events. The paper that follows outlines our current understanding of the crosstalk between PPARγ and epigenetic regulators in NAFLD. Advances in this field are likely to aid in the development of early noninvasive diagnostics and future NAFLD treatment strategies based on PPARγ epigenetic circuit modification.
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Affiliation(s)
- Mohamed Zaiou
- Institut Jean-Lamour, Université de Lorraine, UMR 7198 CNRS, 54505 Vandoeuvre-les-Nancy, France
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GLP-1 Receptor Agonists in Non-Alcoholic Fatty Liver Disease: Current Evidence and Future Perspectives. Int J Mol Sci 2023; 24:ijms24021703. [PMID: 36675217 PMCID: PMC9865319 DOI: 10.3390/ijms24021703] [Citation(s) in RCA: 115] [Impact Index Per Article: 57.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2022] [Revised: 01/10/2023] [Accepted: 01/12/2023] [Indexed: 01/18/2023] Open
Abstract
To date, non-alcoholic fatty liver disease (NAFLD) is the most frequent liver disease, affecting up to 70% of patients with diabetes. Currently, there are no specific drugs available for its treatment. Beyond their anti-hyperglycemic effect and the surprising role of cardio- and nephroprotection, GLP-1 receptor agonists (GLP-1 RAs) have shown a significant impact on body weight and clinical, biochemical and histological markers of fatty liver and fibrosis in patients with NAFLD. Therefore, GLP-1 RAs could be a weapon for the treatment of both diabetes mellitus and NAFLD. The aim of this review is to summarize the evidence currently available on the role of GLP-1 RAs in the treatment of NAFLD and to hypothesize potential future scenarios.
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Endocytosis of LXRs: Signaling in liver and disease. PROGRESS IN MOLECULAR BIOLOGY AND TRANSLATIONAL SCIENCE 2023; 194:347-375. [PMID: 36631198 DOI: 10.1016/bs.pmbts.2022.07.008] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
Abstract
Nuclear receptors are among one of the major transcriptional factors that induces gene regulation in the nucleus. Liver X receptor (LXR) is a transcription factor which regulates essential lipid homeostasis in the body including fatty acid, cholesterol and phospholipid synthesis. Liver X receptor-retinoid X receptor (LXR-RXR) heterodimer is activated by either of the ligand binding on LXR or RXR. The promoter region of the gene which is targeted by LXR is bound to the response element of LXR. The activators bind to the heterodimer once the corepressor is dissociated. The cellular process such as endocytosis aids in intracellular trafficking and endosomal formation in transportation of molecules for essential signaling within the cell. LXR isotypes play a crucial role in maintaining lipid homeostasis by regulating the level of cholesterol. In the liver, the deficiency of LXRα can alter the normal physiological conditions depicting the symptoms of various cardiovascular and liver diseases. LXR can degrade low density lipoprotein receptors (LDLR) by the signaling of LXR-IDOL through endocytic trafficking in lipoprotein uptake. Various gene expressions associated with cholesterol level and lipid synthesis are regulated by LXR transcription factor. With its known diversified ligand binding, LXR is capable of regulating expression of various specific genes responsible for the progression of autoimmune diseases. The agonists and antagonists of LXR stand to be an important factor in transcription of the ABC family, essential for high density lipoprotein (HDL) formation. Endocytosis and signaling mechanism of the LXR family is broad and complex despite their involvement in cellular growth and proliferation. Here in this chapter, we aimed to emphasize the master regulation of LXR activation, regulators, and their implications in various metabolic activities especially in lipid homeostasis. Furthermore, we also briefed the significant role of LXR endocytosis in T cell immune regulation and a variety of human diseases including cardiovascular and neuroadaptive.
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Lee SM, Muratalla J, Karimi S, Diaz-Ruiz A, Frutos MD, Guzman G, Ramos-Molina B, Cordoba-Chacon J. Hepatocyte PPARγ contributes to the progression of non-alcoholic steatohepatitis in male and female obese mice. Cell Mol Life Sci 2023; 80:39. [PMID: 36629912 PMCID: PMC10082675 DOI: 10.1007/s00018-022-04629-z] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2022] [Revised: 10/14/2022] [Accepted: 11/10/2022] [Indexed: 01/12/2023]
Abstract
Non-alcoholic steatohepatitis (NASH) is associated with obesity and increased expression of hepatic peroxisome proliferator-activated receptor γ (PPARγ). However, the relevance of hepatocyte PPARγ in NASH associated with obesity is still poorly understood. In this study, hepatocyte PPARγ was knocked out (PpargΔHep) in male and female mice after the development of high-fat diet-induced obesity. The diet-induced obese mice were then maintained on their original diet or switched to a high fat, cholesterol, and fructose (HFCF) diet to induce NASH. Hepatic PPARγ expression was mostly derived from hepatocytes and increased by high fat diets. PpargΔHep reduced HFCF-induced NASH progression without altering steatosis, reduced the expression of key genes involved in hepatic fibrosis in HFCF-fed male and female mice, and decreased the area of collagen-stained fibrosis in the liver of HFCF-fed male mice. Moreover, transcriptomic and metabolomic data suggested that HFCF-diet regulated hepatic amino acid metabolism in a hepatocyte PPARγ-dependent manner. PpargΔHep increased betaine-homocysteine s-methyltransferase expression and reduced homocysteine levels in HFCF-fed male mice. In addition, in a cohort of 102 obese patients undergoing bariatric surgery with liver biopsies, 16 cases were scored with NASH and were associated with increased insulin resistance and hepatic PPARγ expression. Our study shows that hepatocyte PPARγ expression is associated with NASH in mice and humans. In male mice, hepatocyte PPARγ negatively regulates methionine metabolism and contributes to the progression of fibrosis.
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Affiliation(s)
- Samuel M Lee
- Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Illinois at Chicago, 835 S. Wolcott Ave (North Entrance) Suite E625, M/C 640, Chicago, IL, USA
| | - Jose Muratalla
- Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Illinois at Chicago, 835 S. Wolcott Ave (North Entrance) Suite E625, M/C 640, Chicago, IL, USA
| | - Saman Karimi
- Department of Pathology, University of Illinois at Chicago, Chicago, IL, USA
| | | | - Maria Dolores Frutos
- Department of General and Digestive System Surgery, Virgen de La Arrixaca University Hospital, Murcia, Spain
| | - Grace Guzman
- Department of Pathology, University of Illinois at Chicago, Chicago, IL, USA
| | - Bruno Ramos-Molina
- Obesity and Metabolism Group, Biomedical Research Institute of Murcia (IMIB), Murcia, Spain
| | - Jose Cordoba-Chacon
- Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Illinois at Chicago, 835 S. Wolcott Ave (North Entrance) Suite E625, M/C 640, Chicago, IL, USA.
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Duan Y, Luo J, Pan X, Wei J, Xiao X, Li J, Luo M. Association between inflammatory markers and non-alcoholic fatty liver disease in obese children. Front Public Health 2022; 10:991393. [PMID: 36530698 PMCID: PMC9751435 DOI: 10.3389/fpubh.2022.991393] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2022] [Accepted: 11/11/2022] [Indexed: 12/03/2022] Open
Abstract
Background Given the high prevalence of non-alcoholic fatty liver disease (NAFLD) in obese children, non-invasive markers of disease to date are still limited and worth exploring. Objective This study aimed to evaluate the association between inflammatory markers and NAFLD in obese children. Methods We performed a case-control study in Hunan Children's Hospital from September 2020 to September 2021. Study participants were children with obesity diagnosed with NAFLD by abdominal ultrasound examination. Mean platelet volume (MPV), platelet distribution width (PDW), neutrophil, lymphocyte, monocyte, and platelet counts were extracted from medical records and inflammatory cytokines were measured by enzyme-linked immunosorbent assay (ELISA). Multivariable logistic regression analysis was performed to evaluate the association between inflammatory markers and NAFLD. We also used receiver operating characteristic curve analysis to assess the discriminative ability of inflammatory cytokines for NAFLD. Results Two hundred and sixty-seven obese children were enrolled, including 176 NAFLD patients and 91 simple obesity controls. Multivariable logistic model indicated that increased interleukin (IL)-1β [odds ratio (OR) = 1.15, 95% confidence interval (CI): 1.04-1.27], IL-6 (OR = 1.28, 95% CI: 1.07-1.53), and IL-17 (OR = 1.04, 95% CI: 1.02-1.07) levels were significantly associated with NAFLD. In contrast, we observed non-significant associations for IL-8, IL-12, IL-21, IL-32, tumor necrosis factor-α (TNF-α), neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLR), lymphocyte to monocyte ratio (LMR), mean platelet volume (MPV), and platelet distribution width (PDW) with NAFLD. The area under the curves (AUCs) of IL-1β, IL-6, and IL-17 to discriminate obese children with or without NAFLD were 0.94, 0.94, and 0.97, respectively. Conclusions Our results indicated that IL-1β, IL-6, and IL-17 levels were significantly associated with NAFLD. These inflammatory cytokines may serve as non-invasive markers to determine the development of NAFLD and potentially identify additional avenues for therapeutic intervention.
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Affiliation(s)
- Yamei Duan
- Department of Maternal and Child Health, Xiangya School of Public Health, Central South University, Changsha, Hunan, China
| | - Jiayou Luo
- Department of Maternal and Child Health, Xiangya School of Public Health, Central South University, Changsha, Hunan, China
| | - Xiongfeng Pan
- Department of Maternal and Child Health, Xiangya School of Public Health, Central South University, Changsha, Hunan, China
| | - Jia Wei
- Department of Maternal and Child Health, Xiangya School of Public Health, Central South University, Changsha, Hunan, China
| | - Xiang Xiao
- Department of Maternal and Child Health, Xiangya School of Public Health, Central South University, Changsha, Hunan, China
| | - Jingya Li
- Department of Maternal and Child Health, Xiangya School of Public Health, Central South University, Changsha, Hunan, China
| | - Miyang Luo
- Department of Epidemiology and Health Statistics, Xiangya School of Public Health, Central South University, Changsha, Hunan, China,*Correspondence: Miyang Luo
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Wang J, Dong L, Hu JQ, Wang YYF, Li A, Peng B, Zhang BW, Liu JM, Wang S. Differential regulation and preventive mechanisms of green tea powder with different quality attributes on high-fat diet-induced obesity in mice. Front Nutr 2022; 9:992815. [PMID: 36245513 PMCID: PMC9559937 DOI: 10.3389/fnut.2022.992815] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2022] [Accepted: 09/15/2022] [Indexed: 11/13/2022] Open
Abstract
Tea powder has been reported to have some physiological functions. However, there is no report on whether there are differences in the active ingredients of tea powder with different qualities and whether there are different prebiotic mechanisms. This study was aimed to investigate the effects of different qualities of tea powder on preventing obesity from different aspects, namely antioxidation, inflammation, lipid-lowering, and intestinal flora, using an obesity mouse model. The results showed that all three types of tea powder with different qualities could reduce body weight and decrease serum TC, TG, and LDL-C. However, tea powder with different quality attributes exhibited diverse modulatory effects and mechanisms. Tender tea powder contained more tea polyphenols, and it had a better effect on improving oxidative stress. Tender tea powder significantly decreased the abundances of Blautia, Bilophila, and Oscillibacter, and increased the abundances of Alloprevotella, Lachnoclostridium, Romboutsia, and Ruminococcaceae_UCG-004. Coarse tea powder contained more dietary fiber, and had a better effect on reducing the food intake and improving lipid metabolism, which could reduce lipid synthesis and increase lipid β-oxidation. Coarse tea powder significantly decreased the abundance of Dubosiella and increased the abundances of the Lachnospiraceae_NK4A136 group and Coriobacteriaceae_UCG-002. Our findings provide a theoretical reference for the comprehensive utilization of tea powder.
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Duan Y, Pan X, Luo J, Xiao X, Li J, Bestman PL, Luo M. Association of Inflammatory Cytokines With Non-Alcoholic Fatty Liver Disease. Front Immunol 2022; 13:880298. [PMID: 35603224 PMCID: PMC9122097 DOI: 10.3389/fimmu.2022.880298] [Citation(s) in RCA: 174] [Impact Index Per Article: 58.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2022] [Accepted: 04/11/2022] [Indexed: 01/30/2023] Open
Abstract
Background Inflammatory cytokines have been considered to be significant factors contributing to the development and progression of non-alcoholic fatty liver disease (NAFLD). However, the role of inflammatory cytokines in NAFLD remains inconclusive. Objective This study aimed to evaluate the association between inflammatory cytokines and NAFLD. Methods PubMed, Web of Science, the Cochrane Library, and EMBASE databases were searched until 31 December 2021 to identify eligible studies that reported the association of inflammatory cytokine with NAFLD and its subtypes. We pooled odds ratios (ORs) and hazard risk (HRs) with 95% confidence intervals (CIs) and conducted heterogeneity tests. Sensitivity analysis and analysis for publication bias were also carried out. Results The search in the databases identified 51 relevant studies that investigated the association between 19 different inflammatory cytokines and NAFLD based on 36,074 patients and 47,052 controls. The results of the meta-analysis showed significant associations for C-reactive protein (CRP), interleukin-1β (IL-1β), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and intercellular adhesion molecule-1 (ICAM-1) with NAFLD (ORs of 1.41, 1.08, 1.50, 1.15 and 2.17, respectively). In contrast, we observed non-significant associations for interferon-γ (IFN-γ), insulin-like growth factor (IGF-II), interleukin-2 (IL-2), interleukin-4 (IL-4), interleukin-5 (IL-5), interleukin-7 (IL-7), interleukin-8 (IL-8), interleukin-10 (IL-10), interleukin-12 (IL-12), monocyte chemoattractant protein-1(MCP-1), and transforming growth factor-β (TGF-β) with NAFLD. Our results also showed that CRP, IL-1β, and TNF-α were significantly associated with non-alcoholic steatohepatitis (NASH) and hepatic fibrosis. Conclusions Our results indicated that increased CRP, IL‐1β, IL-6, TNF‐α, and ICAM-1 concentrations were significantly associated with increased risks of NAFLD. These inflammatory mediators may serve as biomarkers for NAFLD subjects and expect to provide new insights into the aetiology of NAFLD as well as early diagnosis and intervention.
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Affiliation(s)
- Yamei Duan
- Department of Maternal and Child Health, Xiangya School of Public Health, Central South University, Changsha, China
| | - Xiongfeng Pan
- Department of Maternal and Child Health, Xiangya School of Public Health, Central South University, Changsha, China
| | - Jiayou Luo
- Department of Maternal and Child Health, Xiangya School of Public Health, Central South University, Changsha, China
| | - Xiang Xiao
- Department of Maternal and Child Health, Xiangya School of Public Health, Central South University, Changsha, China
| | - Jingya Li
- Department of Maternal and Child Health, Xiangya School of Public Health, Central South University, Changsha, China
| | - Prince L. Bestman
- Department of Maternal and Child Health, Xiangya School of Public Health, Central South University, Changsha, China
| | - Miyang Luo
- Department of Epidemiology and Health Statistics, Xiangya School of Public Health, Central South University, Changsha, China
- *Correspondence: Miyang Luo,
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Errafii K, Khalifa O, Al-Akl NS, Arredouani A. Comparative Transcriptome Analysis Reveals That Exendin-4 Improves Steatosis in HepG2 Cells by Modulating Signaling Pathways Related to Lipid Metabolism. Biomedicines 2022; 10:1020. [PMID: 35625757 PMCID: PMC9138370 DOI: 10.3390/biomedicines10051020] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2022] [Revised: 04/09/2022] [Accepted: 04/11/2022] [Indexed: 01/27/2023] Open
Abstract
No therapy exists for non-alcoholic fatty liver disease (NAFLD). However, glucagon-like peptide receptor agonists (GLP-1RAs) showed a beneficial effect on NAFLD, although the underpinning mechanisms remain unclear due to their pleiotropic effects. We examined the implicated signaling pathways using comparative transcriptomics in a cell model of steatosis to overcome pleiotropy. We treated steatotic HepG2 cells with the GLP-1RA Exendin-4 (Ex-4). We compared the transcriptome profiles of untreated steatotic, and Ex-4-treated steatotic cells, and used Ingenuity Pathway Analysis (IPA) to identify the signaling pathways and associated genes involved in the protective effect of Ex-4. Ex-4 treatment significantly reduces steatosis. RNA-seq analysis revealed 209 differentially expressed genes (DEGs) between steatotic and untreated cells, with farnesoid X receptor/retinoid X receptor (FXR/RXR) (p = 8.9 × 10-7) activation being the top regulated canonical pathway identified by IPA. Furthermore, 1644 DEGs were identified between steatotic cells and Ex-4-treated cells, with liver X receptor/retinoid X receptor (LXR/RXR) (p = 2.02 × 10-7) and FXR/RXR (p = 3.28 × 10-7) activation being the two top canonical pathways. The top molecular and cellular functions between untreated and steatotic cells were lipid metabolism, molecular transport, and small molecular biochemistry, while organismal injury and abnormalities, endocrine system disorders, and gastrointestinal disease were the top three molecular and cellular functions between Ex-4-treated and steatotic cells. Genes overlapping steatotic cells and Ex-4-treated cells were associated with several lipid metabolism processes. Unique transcriptomic differences exist between steatotic cells and Ex-4-treated steatotic cells, providing an important resource for understanding the mechanisms that underpin the protective effect of GLP-1RAs on NAFLD and for the identification of novel therapeutic targets for NAFLD.
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Affiliation(s)
- Khaoula Errafii
- College of Health and Life Sciences, Hamad Bin Khalifa University, Qatar Foundation, Doha P.O. Box 34110, Qatar;
- Diabetes Research Center, Qatar Biomedical Research Institute, Hamad Bin Khalifa University, Qatar Foundation, Doha P.O. Box 34110, Qatar; (O.K.); (N.S.A.-A.)
- African Genome Center, Mohammed VI Polytechnic University (UM6P), Ben Guerir 43151, Morocco
| | - Olfa Khalifa
- Diabetes Research Center, Qatar Biomedical Research Institute, Hamad Bin Khalifa University, Qatar Foundation, Doha P.O. Box 34110, Qatar; (O.K.); (N.S.A.-A.)
| | - Neyla S. Al-Akl
- Diabetes Research Center, Qatar Biomedical Research Institute, Hamad Bin Khalifa University, Qatar Foundation, Doha P.O. Box 34110, Qatar; (O.K.); (N.S.A.-A.)
| | - Abdelilah Arredouani
- College of Health and Life Sciences, Hamad Bin Khalifa University, Qatar Foundation, Doha P.O. Box 34110, Qatar;
- Diabetes Research Center, Qatar Biomedical Research Institute, Hamad Bin Khalifa University, Qatar Foundation, Doha P.O. Box 34110, Qatar; (O.K.); (N.S.A.-A.)
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Albhaisi S, Sanyal AJ. Pharmacology of NASH. COMPREHENSIVE PHARMACOLOGY 2022:214-238. [DOI: 10.1016/b978-0-12-820472-6.00121-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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20
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Fuchs CD, Radun R, Dixon ED, Mlitz V, Timelthaler G, Halilbasic E, Herac M, Jonker JW, Ronda OAHO, Tardelli M, Haemmerle G, Zimmermann R, Scharnagl H, Stojakovic T, Verkade HJ, Trauner M. Hepatocyte-specific deletion of adipose triglyceride lipase (adipose triglyceride lipase/patatin-like phospholipase domain containing 2) ameliorates dietary induced steatohepatitis in mice. Hepatology 2022; 75:125-139. [PMID: 34387896 DOI: 10.1002/hep.32112] [Citation(s) in RCA: 31] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/25/2020] [Revised: 07/29/2021] [Accepted: 08/11/2021] [Indexed: 12/18/2022]
Abstract
BACKGROUND AND AIMS Increased fatty acid (FA) flux from adipose tissue to the liver contributes to the development of NAFLD. Because free FAs are key lipotoxic triggers accelerating disease progression, inhibiting adipose triglyceride lipase (ATGL)/patatin-like phospholipase domain containing 2 (PNPLA2), the main enzyme driving lipolysis, may attenuate steatohepatitis. APPROACH AND RESULTS Hepatocyte-specific ATGL knockout (ATGL LKO) mice were challenged with methionine-choline-deficient (MCD) or high-fat high-carbohydrate (HFHC) diet. Serum biochemistry, hepatic lipid content and liver histology were assessed. Mechanistically, hepatic gene and protein expression of lipid metabolism, inflammation, fibrosis, apoptosis, and endoplasmic reticulum (ER) stress markers were investigated. DNA binding activity for peroxisome proliferator-activated receptor (PPAR) α and PPARδ was measured. After short hairpin RNA-mediated ATGL knockdown, HepG2 cells were treated with lipopolysaccharide (LPS) or oleic acid:palmitic acid 2:1 (OP21) to explore the direct role of ATGL in inflammation in vitro. On MCD and HFHC challenge, ATGL LKO mice showed reduced PPARα and increased PPARδ DNA binding activity when compared with challenged wild-type (WT) mice. Despite histologically and biochemically pronounced hepatic steatosis, dietary-challenged ATGL LKO mice showed lower hepatic inflammation, reflected by the reduced number of Galectin3/MAC-2 and myeloperoxidase-positive cells and low mRNA expression levels of inflammatory markers (such as IL-1β and F4/80) when compared with WT mice. In line with this, protein levels of the ER stress markers protein kinase R-like endoplasmic reticulum kinase and inositol-requiring enzyme 1α were reduced in ATGL LKO mice fed with MCD diet. Accordingly, pretreatment of LPS-treated HepG2 cells with the PPARδ agonist GW0742 suppressed mRNA expression of inflammatory markers. Additionally, ATGL knockdown in HepG2 cells attenuated LPS/OP21-induced expression of proinflammatory cytokines and chemokines such as chemokine (C-X-C motif) ligand 5, chemokine (C-C motif) ligand (Ccl) 2, and Ccl5. CONCLUSIONS Low hepatic lipolysis and increased PPARδ activity in ATGL/PNPLA2 deficiency may counteract hepatic inflammation and ER stress despite increased steatosis. Therefore, lowering hepatocyte lipolysis through ATGL inhibition represents a promising therapeutic strategy for the treatment of steatohepatitis.
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Affiliation(s)
- Claudia D Fuchs
- Hans Popper Laboratory of Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - Richard Radun
- Hans Popper Laboratory of Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - Emmanuel D Dixon
- Hans Popper Laboratory of Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - Veronika Mlitz
- Hans Popper Laboratory of Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - Gerald Timelthaler
- Institute for Cancer Research, Internal Medicine I, Medical University of Vienna, Vienna, Austria
| | - Emina Halilbasic
- Hans Popper Laboratory of Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - Merima Herac
- Clinical Institute of Pathology, Medical University Vienna, Vienna, Austria
| | - Johan W Jonker
- Department of Pediatrics, Section of Molecular Metabolism and Nutrition, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
| | - Onne A H O Ronda
- Pediatric Gastroenterology and Hepatology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
| | - Matteo Tardelli
- Hans Popper Laboratory of Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria.,Division of Gastroenterology and Hepatology, Department of Medicine, Weill Cornell Medical College, New York, New York, USA
| | - Guenter Haemmerle
- BioTechMed-Graz, Graz, Austria.,Institute of Molecular Biosciences, University of Graz, Graz, Austria
| | - Robert Zimmermann
- BioTechMed-Graz, Graz, Austria.,Institute of Molecular Biosciences, University of Graz, Graz, Austria
| | - Hubert Scharnagl
- Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz, Austria
| | - Tatjana Stojakovic
- Clinical Institute of Medical and Chemical Laboratory Diagnostics, University Hospital Graz, Graz, Austria
| | - Henkjan J Verkade
- Pediatric Gastroenterology and Hepatology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
| | - Michael Trauner
- Hans Popper Laboratory of Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
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Negi CK, Babica P, Bajard L, Bienertova-Vasku J, Tarantino G. Insights into the molecular targets and emerging pharmacotherapeutic interventions for nonalcoholic fatty liver disease. Metabolism 2022; 126:154925. [PMID: 34740573 DOI: 10.1016/j.metabol.2021.154925] [Citation(s) in RCA: 148] [Impact Index Per Article: 49.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/12/2021] [Revised: 10/27/2021] [Accepted: 10/28/2021] [Indexed: 12/14/2022]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is the most common form of chronic liver disease worldwide. With no Food and Drug Administration approved drugs, current treatment options include dietary restrictions and lifestyle modification. NAFLD is closely associated with metabolic disorders such as obesity, type 2 diabetes, and dyslipidemia. Hence, clinically various pharmacological approaches using existing drugs such as antidiabetic, anti-obesity, antioxidants, and cytoprotective agents have been considered in the management of NAFLD and nonalcoholic steatohepatitis (NASH). However, several pharmacological therapies aiming to alleviate NAFLD-NASH are currently being examined at various phases of clinical trials. Emerging data from these studies with drugs targeting diverse molecular mechanisms show promising outcomes. This review summarizes the current understanding of the pathogenic mechanisms of NAFLD and provides an insight into the pharmacological targets and emerging therapeutics with specific interventional mechanisms. In addition, we also discuss the importance and utility of new approach methodologies and regulatory perspectives for NAFLD-NASH drug development.
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Affiliation(s)
- Chander K Negi
- RECETOX, Faculty of Science, Masaryk University, Kotlarska 2, Brno, Czech Republic
| | - Pavel Babica
- RECETOX, Faculty of Science, Masaryk University, Kotlarska 2, Brno, Czech Republic.
| | - Lola Bajard
- RECETOX, Faculty of Science, Masaryk University, Kotlarska 2, Brno, Czech Republic
| | - Julie Bienertova-Vasku
- RECETOX, Faculty of Science, Masaryk University, Kotlarska 2, Brno, Czech Republic; Department of Pathological Physiology, Faculty of Medicine, Masaryk University, Brno, Czech Republic
| | - Giovanni Tarantino
- Department of Clinical Medicine and Surgery, Federico II University Medical School of Naples, Naples, Italy
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22
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Lee SM, Muratalla J, Diaz-Ruiz A, Remon-Ruiz P, McCann M, Liew CW, Kineman RD, Cordoba-Chacon J. Rosiglitazone Requires Hepatocyte PPARγ Expression to Promote Steatosis in Male Mice With Diet-Induced Obesity. Endocrinology 2021; 162:6356057. [PMID: 34417811 PMCID: PMC8428295 DOI: 10.1210/endocr/bqab175] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/20/2021] [Indexed: 12/12/2022]
Abstract
Thiazolidinediones (TZD) are peroxisome proliferator-activated receptor γ (PPARγ) agonists that may reduce hepatic steatosis through their effects in adipose tissue and therefore have been assessed as potential therapies to treat nonalcoholic fatty liver disease (NAFLD) in humans. However, some studies suggest that expression and activation of hepatocyte PPARγ promotes steatosis and that would limit the benefits of TZD as a NAFLD therapy. To further explore this possibility, we examined the impact of short-term rosiglitazone maleate treatment after the development of moderate or severe diet-induced obesity, in both control and adult-onset hepatocyte-specific PPARγ knockout (PpargΔHep) mice. Independent of the level of obesity and hepatic PPARγ expression, the TZD treatment enhanced insulin sensitivity, associated with an increase in white adipose tissue (WAT) fat accumulation, consistent with clinical observations. However, TZD treatment increased hepatic triglyceride content only in control mice with severe obesity. Under these conditions, PpargΔHep reduced diet-induced steatosis and prevented the steatogenic effects of short-term TZD treatment. In these mice, subcutaneous WAT was enlarged and associated with increased levels of adiponectin, while hepatic levels of phosphorylated adenosine 5'-monophosphate-activated protein kinase were also increased. In addition, in mice with severe obesity, the expression of hepatic Cd36, Cidea, Cidec, Fabp4, Fasn, and Scd-1 was increased by TZD in a PPARγ-dependent manner. Taken together, these results demonstrate that hepatocyte PPARγ expression offsets the antisteatogenic actions of TZD in mice with severe obesity. Therefore, in obese and insulin resistant humans, TZD-mediated activation of hepatocyte PPARγ may limit the therapeutic potential of TZD to treat NAFLD.
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Affiliation(s)
- Samuel M Lee
- Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, University of Illinois at Chicago, Chicago, IL, USA
| | - Jose Muratalla
- Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, University of Illinois at Chicago, Chicago, IL, USA
| | | | - Pablo Remon-Ruiz
- Endocrinology and Clinical Nutrition Department, Virgen del Rocío University Hospital, Institute of Biomedicine of Seville (IBIS), Seville, Spain
| | - Maximilian McCann
- Department of Physiology and Biophysics, University of Illinois at Chicago, Chicago, IL, USA
| | - Chong W Liew
- Department of Physiology and Biophysics, University of Illinois at Chicago, Chicago, IL, USA
| | - Rhonda D Kineman
- Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, University of Illinois at Chicago, Chicago, IL, USA
- Research and Development Division. Jesse Brown VA Medical Center, Chicago, IL, USA
| | - Jose Cordoba-Chacon
- Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, University of Illinois at Chicago, Chicago, IL, USA
- Correspondence: Jose Cordoba-Chacon, PhD, Department of Medicine, Section of Endocrinology, Diabetes and Metabolism. 835 S. Wolcott Ave (North Entrance) Suite E625. M/C 640. Chicago, IL, USA.
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23
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Zhang Y, Fan X, Qiu L, Zhu W, Huang L, Miao Y. Liver X receptor α promotes milk fat synthesis in buffalo mammary epithelial cells by regulating the expression of FASN. J Dairy Sci 2021; 104:12980-12993. [PMID: 34593221 DOI: 10.3168/jds.2021-20596] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2021] [Accepted: 08/16/2021] [Indexed: 01/14/2023]
Abstract
Liver X receptor α (LXRα; NR1H3) is an important transcription factor that can facilitate milk fat synthesis by regulating the transcription of FASN in mice and goats. Nevertheless, the lipid synthesis related to LXRα and its regulation on FASN in the buffalo mammary gland remain elusive. Here, we demonstrated that the mRNA and protein expression of LXRα in buffalo mammary tissue increased in lactation compared with that in the dry-off period. Overexpression of NR1H3 enhanced the lipid droplet formation and triacylglycerol concentration in buffalo mammary epithelial cells (BuMEC), whereas the knockdown of NR1H3 resulted in a decrease in the number of lipid droplets. At the same time, NR1H3 also affected the expression of regulatory factors (INSIG1, INSIG2, SREBF1, and PPARG) related to milk fat synthesis and that of genes involved in de novo synthesis (FASN, ACACA, and SCD), and uptake and transport (LPL, CD36, and FABP3) of fatty acids as well as triacylglycerol synthesis (GPAM, APGAT6, and DGAT1). Luciferase reporter assays indicated that overexpression of NR1H3 resulted in an increase in the activity of FASN promoter, whereas the knockdown of NR1H3 had an opposite effect. When NR1H3 was overexpressed, mutations in LXRE or SRE could decrease the promoter activity of FASN. Furthermore, mutagenesis of both LXRE and SRE within the FASN promoter completely eliminated the induced activity of LXRα. Our results reveal that buffalo LXRα promotes milk fat synthesis through regulating the expression of FASN by directly interacting with FASN promoter and affecting the SREBF1 expression. This study underscores a crucial role of LXRα in regulating lipid synthesis of the buffalo mammary gland.
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Affiliation(s)
- Yongyun Zhang
- Faculty of Animal Science and Technology, Yunnan Agricultural University, Kunming 650201, Yunnan, China; Teaching Demonstration Center of the Basic Experiments of Agricultural Majors, Yunnan Agricultural University, Kunming 650201, Yunnan, China
| | - Xinyang Fan
- Faculty of Animal Science and Technology, Yunnan Agricultural University, Kunming 650201, Yunnan, China
| | - Lihua Qiu
- Faculty of Animal Science and Technology, Yunnan Agricultural University, Kunming 650201, Yunnan, China
| | - Wei Zhu
- College of Veterinary Medicine, Yunnan Agricultural University, Kunming 650201, Yunnan, China
| | - Lige Huang
- Faculty of Animal Science and Technology, Yunnan Agricultural University, Kunming 650201, Yunnan, China
| | - Yongwang Miao
- Faculty of Animal Science and Technology, Yunnan Agricultural University, Kunming 650201, Yunnan, China.
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24
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Mai CT, Zheng DC, Li XZ, Zhou H, Xie Y. Liver X receptors conserve the therapeutic target potential for the treatment of rheumatoid arthritis. Pharmacol Res 2021; 170:105747. [PMID: 34186192 DOI: 10.1016/j.phrs.2021.105747] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/08/2021] [Revised: 06/21/2021] [Accepted: 06/24/2021] [Indexed: 01/03/2023]
Abstract
Rheumatoid arthritis (RA) is a chronic multi-system autoimmune disease with extremely complex pathogenesis. Significantly altered lipid paradox related to the inflammatory burden is reported in RA patients, inducing 50% higher cardiovascular risks. Recent studies have also demonstrated that lipid metabolism can regulate many functions of immune cells in which metabolic pathways have altered. The nuclear liver X receptors (LXRs), including LXRα and LXRβ, play a central role in regulating lipid homeostasis and inflammatory responses. Undoubtedly, LXRs have been considered as an attractive therapeutic target for the treatment of RA. However, there are some contradictory effects of LXRs agonists observed in previous animal studies where both pro-inflammatory role and anti-inflammatory role were revealed for LXRs activation in RA. Therefore, in addition to updating the knowledge of LXRs as the prominent regulators of lipid homeostasis, the purpose of this review is to summarize the effects of LXRs agonists in RA-associated immune cells, to explore the underlying reasons for the contradictory therapeutic effects of LXRs agonists observed in RA animal models, and to discuss future strategy for the treatment of RA with LXRs modulators.
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Affiliation(s)
- Chu-Tian Mai
- State Key Laboratory of Quality Research in Chinese Medicines, Macau University of Science and Technology, Taipa, Macau; Faculty of Chinese Medicines, Macau University of Science and Technology, Taipa, Macau
| | - De-Chong Zheng
- State Key Laboratory of Quality Research in Chinese Medicines, Macau University of Science and Technology, Taipa, Macau; Faculty of Chinese Medicines, Macau University of Science and Technology, Taipa, Macau
| | - Xin-Zhi Li
- State Key Laboratory of Quality Research in Chinese Medicines, Macau University of Science and Technology, Taipa, Macau
| | - Hua Zhou
- State Key Laboratory of Quality Research in Chinese Medicines, Macau University of Science and Technology, Taipa, Macau; Faculty of Chinese Medicines, Macau University of Science and Technology, Taipa, Macau
| | - Ying Xie
- State Key Laboratory of Quality Research in Chinese Medicines, Macau University of Science and Technology, Taipa, Macau.
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25
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Ye J, Zhao Y, Chen X, Zhou H, Yang Y, Zhang X, Huang Y, Zhang N, Lui EMK, Xiao M. Pu-erh tea ameliorates obesity and modulates gut microbiota in high fat diet fed mice. Food Res Int 2021; 144:110360. [PMID: 34053553 DOI: 10.1016/j.foodres.2021.110360] [Citation(s) in RCA: 108] [Impact Index Per Article: 27.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2020] [Revised: 03/23/2021] [Accepted: 03/30/2021] [Indexed: 01/03/2023]
Abstract
Obesity is regarded to be associated with fat accumulation, chronic inflammation, and gut microbiota dysbiosis. Raw and ripened pu-erh tea extract (PETe) have the effect of reducing body weight gain and fat accumulation, which are associated with gut microbiota. However, little is known about the difference of raw and ripened PETe on the regulation of gut microbiota. Here, our results suggested that supplementation of raw and ripened PETe displayed similar anti-obesogenic effect in high fat diet (HFD)-induced obesity mice, by attenuating the body weight gain, fat accumulation, oxidative injury, and low-grade inflammation, improving the glucose tolerance, alleviating the metabolic endotoxemia, and regulating the mRNA and protein expression levels of the lipid metabolism-related genes. 16S rRNA sequencing of fecal samples indicated that raw and ripened PETe intervention displayed different regulatory effect on the HFD-induced gut microbiota dysbiosis at different taxonomic levels. The microbial diversity, the relative abundance of Firmicutes and Bacteroidetes as well as F/B ratio were reversed more closer to normal by ripened PETe. Phylotypes of Bacteroidaceae, Ruminococcaceae, Lachnospiraceae, Muribaculaceae, and Rikenellaceae which are negatively correlated with obesity were enhanced notably by the intervention of ripened PETe, while Erysipelotrichaceae and Lactobacillaceae which have positive correlation with obesity were decreased dramatically. In addition, the treatment of ripened PETe had better effect on the increase of benefical Bacteroides, Alistipes, and Akkemansia and decrease of obesity associated Faecalibaculum and Erysipelatoclostridium (p < 0.05). These findings suggested that pu-erh tea especially ripened pu-erh tea could serve as a great candidate for alleviation of obesity in association with the modulation of gut microbiota.
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Affiliation(s)
- Jing Ye
- College of Chemical Engineering, Huaqiao University, Xiamen 361021, China; Xiamen Engineering and Technological Research Center for Comprehensive Utilization of Marine Biological Resources, Xiamen 361021, China.
| | - Yan Zhao
- College of Chemical Engineering, Huaqiao University, Xiamen 361021, China
| | - Xiangming Chen
- College of Chemical Engineering, Huaqiao University, Xiamen 361021, China
| | - Huiyu Zhou
- College of Chemical Engineering, Huaqiao University, Xiamen 361021, China
| | - Yucheng Yang
- College of Chemical Engineering, Huaqiao University, Xiamen 361021, China; Xiamen Engineering and Technological Research Center for Comprehensive Utilization of Marine Biological Resources, Xiamen 361021, China
| | - Xueqin Zhang
- College of Chemical Engineering, Huaqiao University, Xiamen 361021, China; Xiamen Engineering and Technological Research Center for Comprehensive Utilization of Marine Biological Resources, Xiamen 361021, China
| | - Yayan Huang
- College of Chemical Engineering, Huaqiao University, Xiamen 361021, China; Xiamen Engineering and Technological Research Center for Comprehensive Utilization of Marine Biological Resources, Xiamen 361021, China
| | - Na Zhang
- College of Chemical Engineering, Huaqiao University, Xiamen 361021, China; Xiamen Engineering and Technological Research Center for Comprehensive Utilization of Marine Biological Resources, Xiamen 361021, China
| | - Edmund M K Lui
- Physiology and Pharmacology, Western University, London, Ontario N6A 5B9, Canada
| | - Meitian Xiao
- College of Chemical Engineering, Huaqiao University, Xiamen 361021, China; Xiamen Engineering and Technological Research Center for Comprehensive Utilization of Marine Biological Resources, Xiamen 361021, China
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Tanshinone IIA Downregulates Lipogenic Gene Expression and Attenuates Lipid Accumulation through the Modulation of LXRα/SREBP1 Pathway in HepG2 Cells. Biomedicines 2021; 9:biomedicines9030326. [PMID: 33806955 PMCID: PMC8004631 DOI: 10.3390/biomedicines9030326] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2021] [Revised: 03/21/2021] [Accepted: 03/21/2021] [Indexed: 12/12/2022] Open
Abstract
Abnormal and excessive accumulation of lipid droplets within hepatic cells is the main feature of steatosis and nonalcoholic fatty liver disease (NAFLD) or metabolic-associated fatty liver disease (MAFLD). Dysregulation of lipogenesis contributes to hepatic steatosis and plays an essential role in the pathological progress of MAFLD. Tanshinone IIA is a bioactive phytochemical isolated from Salvia miltiorrhiza Bunge and exhibits anti-inflammatory, antiatherosclerotic and antihyperlipidemic effects. In this study, we aimed to investigate the lipid-lowering effects of tanshinone IIA on the regulation of lipogenesis, lipid accumulation, and the underlying mechanisms in hepatic cells. We demonstrated that tanshinone IIA can significantly inhibit the gene expression involved in de novo lipogenesis including FASN, ACC1, and SCD1, in HepG2 and Huh 7 cells. Tanshinone IIA could increase phosphorylation of ACC1 protein in HepG2 cells. We further demonstrated that tanshinone IIA also could suppress the fatty-acid-induced lipogenesis and TG accumulation in HepG2 cells. Furthermore, tanshinone IIA markedly downregulated the mRNA and protein expression of SREBP1, an essential transcription factor regulating lipogenesis in hepatic cells. Moreover, we found that tanshinone IIA attenuated liver X receptor α (LXRα)-mediated lipogenic gene expression and lipid droplet accumulation, but did not change the levels of LXRα mRNA or protein in HepG2 cells. The molecular docking data predicted tanshinone IIA binding to the ligand-binding domain of LXRα, which may result in the attenuation of LXRα-induced transcriptional activation. Our findings support the supposition that tanshinone IIA possesses a lipid-modulating effect that suppresses lipogenesis and attenuates lipid accumulation by modulating the LXRα/SREBP1 pathway in hepatic cells. Tanshinone IIA can be potentially used as a supplement or drug for the prevention or treatment of MAFLD.
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27
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Lee SM, Pusec CM, Norris GH, De Jesus A, Diaz-Ruiz A, Muratalla J, Sarmento-Cabral A, Guzman G, Layden BT, Cordoba-Chacon J. Hepatocyte-Specific Loss of PPARγ Protects Mice From NASH and Increases the Therapeutic Effects of Rosiglitazone in the Liver. Cell Mol Gastroenterol Hepatol 2021; 11:1291-1311. [PMID: 33444819 PMCID: PMC8005819 DOI: 10.1016/j.jcmgh.2021.01.003] [Citation(s) in RCA: 40] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/25/2020] [Revised: 01/04/2021] [Accepted: 01/05/2021] [Indexed: 02/06/2023]
Abstract
BACKGROUND & AIMS Nonalcoholic steatohepatitis (NASH) is commonly observed in patients with type 2 diabetes, and thiazolidinediones (TZD) are considered a potential therapy for NASH. Although TZD increase insulin sensitivity and partially reduce steatosis and alanine aminotransferase, the efficacy of TZD on resolving liver pathology is limited. In fact, TZD may activate peroxisome proliferator-activated receptor gamma (PPARγ) in hepatocytes and promote steatosis. Therefore, we assessed the role that hepatocyte-specific PPARγ plays in the development of NASH, and how it alters the therapeutic effects of TZD on the liver of mice with diet-induced NASH. METHODS Hepatocyte-specific PPARγ expression was knocked out in adult mice before and after the development of NASH induced with a high fat, cholesterol, and fructose (HFCF) diet. RESULTS HFCF diet increased PPARγ expression in hepatocytes, and rosiglitazone further activated PPARγ in hepatocytes of HFCF-fed mice in vivo and in vitro. Hepatocyte-specific loss of PPARγ reduced the progression of HFCF-induced NASH in male mice and increased the benefits derived from the effects of TZD on extrahepatic tissues and non-parenchymal cells. RNAseq and metabolomics indicated that HFCF diet promoted inflammation and fibrogenesis in a hepatocyte PPARγ-dependent manner and was associated with dysregulation of hepatic metabolism. Specifically, hepatocyte-specific loss of PPARγ plays a positive role in the regulation of methionine metabolism, and that could reduce the progression of NASH. CONCLUSIONS Because of the negative effect of hepatocyte PPARγ in NASH, inhibition of mechanisms promoted by endogenous PPARγ in hepatocytes may represent a novel strategy that increases the efficiency of therapies for NAFLD.
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Affiliation(s)
- Samuel M. Lee
- Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, University of Illinois at Chicago, Chicago, Illinois
| | - Carolina M. Pusec
- Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, University of Illinois at Chicago, Chicago, Illinois
| | - Gregory H. Norris
- Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, University of Illinois at Chicago, Chicago, Illinois
| | | | | | - Jose Muratalla
- Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, University of Illinois at Chicago, Chicago, Illinois
| | - Andre Sarmento-Cabral
- Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, University of Illinois at Chicago, Chicago, Illinois
| | - Grace Guzman
- Department of Pathology, University of Illinois at Chicago, Chicago, Illinois
| | - Brian T. Layden
- Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, University of Illinois at Chicago, Chicago, Illinois,Research and Development, Jesse Brown VA Medical Center, Chicago, Illinois
| | - Jose Cordoba-Chacon
- Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, University of Illinois at Chicago, Chicago, Illinois,Correspondence Address correspondence to: Jose Cordoba-Chacon, PhD, Department of Medicine, Section of Endocrinology, Diabetes and Metabolism, 835 South Wolcott Avenue (North Entrance), Suite E625, M/C 640, Chicago, Illinois 60612. fax (312) 413-0437.
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28
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Zhao L, Lei W, Deng C, Wu Z, Sun M, Jin Z, Song Y, Yang Z, Jiang S, Shen M, Yang Y. The roles of liver X receptor α in inflammation and inflammation-associated diseases. J Cell Physiol 2020; 236:4807-4828. [PMID: 33305467 DOI: 10.1002/jcp.30204] [Citation(s) in RCA: 37] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2020] [Revised: 10/19/2020] [Accepted: 11/24/2020] [Indexed: 12/14/2022]
Abstract
Liver X receptor α (LXRα; also known as NR1H3), an isoform of LXRs, is a member of the nuclear receptor family of transcription factors and plays essential roles in the transcriptional control of cholesterol homeostasis. Previous in-depth phenotypic analyses of mouse models with deficient LXRα have also demonstrated various physiological functions of this receptor within inflammatory responses. LXRα activation exerts a combination of metabolic and anti-inflammatory actions resulting in the modulation and the amelioration of inflammatory disorders. The tight "repercussions" between LXRα and inflammation, as well as cholesterol homeostasis, have suggested that LXRα could be pharmacologically targeted in pathologies such as atherosclerosis, acute lung injury, and Alzheimer's disease. This review gives an overview of the recent advances in understanding the roles of LXRα in inflammation and inflammation-associated diseases, which will help in the design of future experimental researches on the potential of LXRα and advance the investigation of LXRα as pharmacological inflammatory targets.
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Affiliation(s)
- Lin Zhao
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education Life of Sciences, Northwest University, Xi'an, China.,Department of Cardiovascular Surgery, Xijing Hospital, The Fourth Military Medical University, Xi'an, China
| | - Wangrui Lei
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education Life of Sciences, Northwest University, Xi'an, China
| | - Chao Deng
- Department of Cardiovascular Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Zhen Wu
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education Life of Sciences, Northwest University, Xi'an, China
| | - Meng Sun
- Department of Cardiology, The First Hospital of Shanxi Medical University, Taiyuan, China
| | - Zhenxiao Jin
- Department of Cardiovascular Surgery, Xijing Hospital, The Fourth Military Medical University, Xi'an, China
| | - Yanbin Song
- Department of Cardiology, Affiliated Hospital, Yan'an University, China
| | - Zhi Yang
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education Life of Sciences, Northwest University, Xi'an, China
| | - Shuai Jiang
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education Life of Sciences, Northwest University, Xi'an, China
| | - Mingzhi Shen
- Hainan Hospital of PLA General Hospital, The Second School of Clinical Medicine, Southern Medical University, Sanya, Hainan, China.,Hainan Branch of National Clinical Reasearch Center of Geriatrics Disease, Sanya, Hainan, China
| | - Yang Yang
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education Life of Sciences, Northwest University, Xi'an, China
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29
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Smith GI, Shankaran M, Yoshino M, Schweitzer GG, Chondronikola M, Beals JW, Okunade AL, Patterson BW, Nyangau E, Field T, Sirlin CB, Talukdar S, Hellerstein MK, Klein S. Insulin resistance drives hepatic de novo lipogenesis in nonalcoholic fatty liver disease. J Clin Invest 2020; 130:1453-1460. [PMID: 31805015 DOI: 10.1172/jci134165] [Citation(s) in RCA: 507] [Impact Index Per Article: 101.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2019] [Accepted: 11/20/2019] [Indexed: 12/11/2022] Open
Abstract
BACKGROUNDAn increase in intrahepatic triglyceride (IHTG) is the hallmark feature of nonalcoholic fatty liver disease (NAFLD) and is decreased by weight loss. Hepatic de novo lipogenesis (DNL) contributes to steatosis in individuals with NAFLD. The physiological factors that stimulate hepatic DNL and the effect of weight loss on hepatic DNL are not clear.METHODSHepatic DNL, 24-hour integrated plasma insulin and glucose concentrations, and both liver and whole-body insulin sensitivity were determined in individuals who were lean (n = 14), obese with normal IHTG content (n = 26), or obese with NAFLD (n = 27). Hepatic DNL was assessed using the deuterated water method corrected for the potential confounding contribution of adipose tissue DNL. Liver and whole-body insulin sensitivity was assessed using the hyperinsulinemic-euglycemic clamp procedure in conjunction with glucose tracer infusion. Six subjects in the obese-NAFLD group were also evaluated before and after a diet-induced weight loss of 10%.RESULTSThe contribution of hepatic DNL to IHTG-palmitate was 11%, 19%, and 38% in the lean, obese, and obese-NAFLD groups, respectively. Hepatic DNL was inversely correlated with hepatic and whole-body insulin sensitivity, but directly correlated with 24-hour plasma glucose and insulin concentrations. Weight loss decreased IHTG content, in conjunction with a decrease in hepatic DNL and 24-hour plasma glucose and insulin concentrations.CONCLUSIONSThese data suggest hepatic DNL is an important regulator of IHTG content and that increases in circulating glucose and insulin stimulate hepatic DNL in individuals with NAFLD. Weight loss decreased IHTG content, at least in part, by decreasing hepatic DNL.TRIAL REGISTRATIONClinicalTrials.gov NCT02706262.FUNDINGThis study was supported by NIH grants DK56341 (Nutrition Obesity Research Center), DK20579 (Diabetes Research Center), DK52574 (Digestive Disease Research Center), and RR024992 (Clinical and Translational Science Award), and by grants from the Academy of Nutrition and Dietetics Foundation, the College of Natural Resources of UCB, and the Pershing Square Foundation.
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Affiliation(s)
- Gordon I Smith
- Atkins Center of Excellence in Obesity Medicine, Center for Human Nutrition, John T. Milliken Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, USA
| | - Mahalakshmi Shankaran
- Department of Nutritional Sciences and Toxicology, College of Natural Resources, University of California at Berkeley, Berkeley, California, USA
| | - Mihoko Yoshino
- Atkins Center of Excellence in Obesity Medicine, Center for Human Nutrition, John T. Milliken Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, USA
| | - George G Schweitzer
- Atkins Center of Excellence in Obesity Medicine, Center for Human Nutrition, John T. Milliken Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, USA
| | - Maria Chondronikola
- Atkins Center of Excellence in Obesity Medicine, Center for Human Nutrition, John T. Milliken Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, USA
| | - Joseph W Beals
- Atkins Center of Excellence in Obesity Medicine, Center for Human Nutrition, John T. Milliken Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, USA
| | - Adewole L Okunade
- Atkins Center of Excellence in Obesity Medicine, Center for Human Nutrition, John T. Milliken Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, USA
| | - Bruce W Patterson
- Atkins Center of Excellence in Obesity Medicine, Center for Human Nutrition, John T. Milliken Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, USA
| | - Edna Nyangau
- Department of Nutritional Sciences and Toxicology, College of Natural Resources, University of California at Berkeley, Berkeley, California, USA
| | - Tyler Field
- Department of Nutritional Sciences and Toxicology, College of Natural Resources, University of California at Berkeley, Berkeley, California, USA
| | - Claude B Sirlin
- Liver Imaging Group, University of California, San Diego, La Jolla, California, USA
| | | | - Marc K Hellerstein
- Department of Nutritional Sciences and Toxicology, College of Natural Resources, University of California at Berkeley, Berkeley, California, USA
| | - Samuel Klein
- Atkins Center of Excellence in Obesity Medicine, Center for Human Nutrition, John T. Milliken Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, USA
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30
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Gao L, Li B, Wang J, Shen D, Yang M, Sun R, Tung H, Xu M, Ren S, Zhang M, Yang D, Lu B, Wang H, Liu Y, Xie W. Activation of Liver X Receptor α Sensitizes Mice to T-Cell Mediated Hepatitis. Hepatol Commun 2020; 4:1664-1679. [PMID: 33163836 PMCID: PMC7603537 DOI: 10.1002/hep4.1584] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/30/2020] [Revised: 06/14/2020] [Accepted: 07/06/2020] [Indexed: 12/27/2022] Open
Abstract
Autoimmune hepatitis (AIH) is an inflammatory disease of the liver. Liver X receptors (LXRs), including the α and β isoforms, are previously known for their anti-inflammatory activities. The goal of this study is to determine whether and how LXR plays a role in AIH. LXRα gain-of-function and loss-of-function mouse models were used, in conjunction with the concanavalin A (ConA) model of T-cell mediated hepatitis. We first showed that the hepatic expression of LXRα was decreased in the ConA model of hepatitis and in human patients with AIH. In the ConA model, we were surprised to find that activation of LXRα in the constitutively activated VP-LXRα whole-body knock-in (LXRα-KI) mice exacerbated ConA-induced AIH, whereas the LXRα-/- mice showed attenuated ConA-induced AIH. Interestingly, hepatocyte-specific activation of LXRα in the fatty acid binding protein-VP-LXRα transgenic mice did not exacerbate ConA-induced hepatitis. Mechanistically, the sensitizing effect of the LXRα-KI allele was invariant natural killer T (iNKT)-cell dependent, because the sensitizing effect was abolished when the LXRα-KI allele was bred into the NKT-deficient CD1d-/- background. In addition, LXRα-enhanced ConA-induced hepatitis was dependent on interferon gamma. In contrast, adoptive transfer of hepatic iNKT cells isolated from LXRα-KI mice was sufficient to sensitize CD1d-/- mice to ConA-induced AIH. Conclusion: Activation of LXRα sensitizes mice to ConA-induced AIH in iNKT and interferon gamma-dependent manner. Our results suggest that LXRα plays an important role in the development of AIH.
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Affiliation(s)
- Li Gao
- Center for Pharmacogenetics and Department of Pharmaceutical SciencesUniversity of PittsburghPittsburghPAUSA
- Department of GastroenterologyPeking University People's HospitalBeijingChina
| | - Bin Li
- Center for Pharmacogenetics and Department of Pharmaceutical SciencesUniversity of PittsburghPittsburghPAUSA
- Department of Orthopedic SurgeryZhongnan Hospital of Wuhan UniversityWuhanChina
- Department of PharmacologyBasic Medical School of Wuhan UniversityWuhanChina
| | - Jingyuan Wang
- Center for Pharmacogenetics and Department of Pharmaceutical SciencesUniversity of PittsburghPittsburghPAUSA
| | - Danhua Shen
- Department of PathologyPeking University People’s HospitalBeijingChina
| | - Min Yang
- Department of ImmunologyUniversity of PittsburghPittsburghPAUSA
| | - Runzi Sun
- Department of ImmunologyUniversity of PittsburghPittsburghPAUSA
| | - Hung‐Chun Tung
- Center for Pharmacogenetics and Department of Pharmaceutical SciencesUniversity of PittsburghPittsburghPAUSA
| | - Meishu Xu
- Center for Pharmacogenetics and Department of Pharmaceutical SciencesUniversity of PittsburghPittsburghPAUSA
| | - Songrong Ren
- Center for Pharmacogenetics and Department of Pharmaceutical SciencesUniversity of PittsburghPittsburghPAUSA
| | - Min Zhang
- Center for Pharmacogenetics and Department of Pharmaceutical SciencesUniversity of PittsburghPittsburghPAUSA
| | - Da Yang
- Center for Pharmacogenetics and Department of Pharmaceutical SciencesUniversity of PittsburghPittsburghPAUSA
| | - Binfeng Lu
- Department of ImmunologyUniversity of PittsburghPittsburghPAUSA
| | - Hui Wang
- Department of PharmacologyBasic Medical School of Wuhan UniversityWuhanChina
| | - Yulan Liu
- Department of GastroenterologyPeking University People's HospitalBeijingChina
| | - Wen Xie
- Center for Pharmacogenetics and Department of Pharmaceutical SciencesUniversity of PittsburghPittsburghPAUSA
- Department of Pharmacology & Chemical BiologyUniversity of PittsburghPittsburghPAUSA
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31
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Zhang H, Léveillé M, Courty E, Gunes A, N Nguyen B, Estall JL. Differences in metabolic and liver pathobiology induced by two dietary mouse models of nonalcoholic fatty liver disease. Am J Physiol Endocrinol Metab 2020; 319:E863-E876. [PMID: 32924526 DOI: 10.1152/ajpendo.00321.2020] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is a growing epidemic linked to metabolic disease. The first stage of NAFLD is characterized by lipid accumulation in hepatocytes, but this can progress into nonalcoholic steatohepatitis (NASH), cirrhosis, and hepatocellular carcinoma (HCC). Western diets, high in fats, sugars, and cholesterol, are linked to NAFLD development. Murine models are often used to study NAFLD; however, there remains debate on which diet-induced model best mimics both human disease progression and pathogenesis. In this study, we performed a side-by-side comparison of two popular diet models of murine NAFLD/NASH and associated HCC, a high-fat diet supplemented with 30% fructose water (HFHF) and a Western diet high in cholesterol (WDHC), and these were compared with a common grain-based chow diet (GBD). Mice on both experimental diets developed liver steatosis, and WDHC-fed mice had greater levels of hepatic inflammation and fibrosis than HFHF-fed mice. In contrast, HFHF-fed mice were more obese and developed more severe metabolic syndrome, with less pronounced liver disease. Despite these differences, WDHC-fed and HFHF-fed mice had similar tumor burdens in a model of diet-potentiated liver cancer. Response to diet and resulting phenotypes were generally similar between sexes, albeit delayed in females. This study shows that modest differences in diet can significantly uncouple glucose homeostasis and liver damage. In conclusion, long-term feeding of either HFHF or WDHC is a reliable method to induce NASH and diet-potentiated liver cancer in mice of both sexes; however, the choice of diet involves a trade-off between severity of metabolic syndrome and liver damage.
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Affiliation(s)
- Hannah Zhang
- Institut de recherches cliniques de Montréal (IRCM), Montreal, Quebec, Canada
- Department of Anatomy and Cell Biology, McGill University, Montreal, Quebec, Canada
| | - Mélissa Léveillé
- Institut de recherches cliniques de Montréal (IRCM), Montreal, Quebec, Canada
- Department of Medicine, University of Montreal, Montreal, Quebec, Canada
| | - Emilie Courty
- Institut de recherches cliniques de Montréal (IRCM), Montreal, Quebec, Canada
- Division of Experimental Medicine, McGill University, Montreal, Quebec, Canada
| | - Aysim Gunes
- Institut de recherches cliniques de Montréal (IRCM), Montreal, Quebec, Canada
- Division of Experimental Medicine, McGill University, Montreal, Quebec, Canada
| | - Bich N Nguyen
- Department of Pathology and Cell Biology, University of Montreal, Montreal, Quebec, Canada
- University of Montreal Health Network (CHUM), Montreal, Quebec Canada
| | - Jennifer L Estall
- Institut de recherches cliniques de Montréal (IRCM), Montreal, Quebec, Canada
- Department of Medicine, University of Montreal, Montreal, Quebec, Canada
- Department of Anatomy and Cell Biology, McGill University, Montreal, Quebec, Canada
- Division of Experimental Medicine, McGill University, Montreal, Quebec, Canada
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32
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Shao M, Ye Z, Qin Y, Wu T. Abnormal metabolic processes involved in the pathogenesis of non-alcoholic fatty liver disease (Review). Exp Ther Med 2020; 20:26. [PMID: 32934691 PMCID: PMC7471863 DOI: 10.3892/etm.2020.9154] [Citation(s) in RCA: 37] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2019] [Accepted: 05/28/2020] [Indexed: 12/13/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is one of the most common chronic liver diseases and can lead to liver cirrhosis or liver cancer in severe cases. In recent years, the incidence of NAFLD has increased substantially. The trend has continued to increase and has become a key point of concern for health systems. NAFLD is often associated with metabolic abnormalities caused by increased visceral obesity, including insulin resistance, diabetes mellitus, hypertension, dyslipidemia, atherosclerosis and systemic microinflammation. Therefore, the pathophysiological mechanisms of NAFLD must be clarified to develop new drug treatment strategies. Recently, researchers have conducted numerous studies on the pathogenesis of NAFLD and have identified various important regulatory factors and potential molecular mechanisms, providing new targets and a theoretical basis for the treatment of NAFLD. However, the pathogenesis of NAFLD is extremely complex and involves the interrelationship and influence of multiple organs and systems. Therefore, the condition must be explored further. In the present review, the abnormal metabolic process, including glucose, lipid, amino acid, bile acid and iron metabolism are reviewed. It was concluded that NAFLD is associated with an imbalanced metabolic network that involves glucose, lipids, amino acids, bile acids and iron, and lipid metabolism is the core metabolic process. The current study aimed to provide evidence and hypotheses for research and clinical treatment of NAFLD.
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Affiliation(s)
- Mingmei Shao
- Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, P.R. China
| | - Zixiang Ye
- Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, P.R. China
| | - Yanhong Qin
- Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, P.R. China
| | - Tao Wu
- Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, P.R. China
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Gómez‐Santos B, Saenz de Urturi D, Nuñez‐García M, Gonzalez‐Romero F, Buque X, Aurrekoetxea I, Gutiérrez de Juan V, Gonzalez‐Rellan MJ, García‐Monzón C, González‐Rodríguez Á, Mosteiro L, Errazti G, Mifsut P, Gaztambide S, Castaño L, Martin C, Nogueiras R, Martinez‐Chantar ML, Syn W, Aspichueta P. Liver osteopontin is required to prevent the progression of age-related nonalcoholic fatty liver disease. Aging Cell 2020; 19:e13183. [PMID: 32638492 PMCID: PMC7431823 DOI: 10.1111/acel.13183] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2019] [Revised: 04/14/2020] [Accepted: 06/06/2020] [Indexed: 12/17/2022] Open
Abstract
Osteopontin (OPN), a senescence-associated secretory phenotype factor, is increased in patients with nonalcoholic fatty liver disease (NAFLD). Cellular senescence has been associated with age-dependent hepatosteatosis. Thus, we investigated the role of OPN in the age-related hepatosteatosis. For this, human serum samples, animal models of aging, and cell lines in which senescence was induced were used. Metabolic fluxes, lipid, and protein concentration were determined. Among individuals with a normal liver, we observed a positive correlation between serum OPN levels and increasing age. This correlation with age, however, was absent in patients with NAFLD. In wild-type (WT) mice, serum and liver OPN were increased at 10 months old (m) along with liver p53 levels and remained elevated at 20m. Markers of liver senescence increased in association with synthesis and concentration of triglycerides (TG) in 10m OPN-deficient (KO) hepatocytes when compared to WT hepatocytes. These changes in senescence and lipid metabolism in 10m OPN-KO mice liver were associated with the decrease of 78 kDa glucose-regulated protein (GRP78), induction of ER stress, and the increase in fatty acid synthase and CD36 levels. OPN deficiency in senescent cells also diminished GRP78, the accumulation of intracellular TG, and the increase in CD36 levels. In 20m mice, OPN loss led to increased liver fibrosis. Finally, we showed that OPN expression in vitro and in vivo was regulated by p53. In conclusion, OPN deficiency leads to earlier cellular senescence, ER stress, and TG accumulation during aging. The p53-OPN axis is required to inhibit the onset of age-related hepatosteatosis.
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Affiliation(s)
- Beatriz Gómez‐Santos
- Department of Physiology Faculty of Medicine and Nursing University of Basque Country UPV/EHU Leioa Spain
| | - Diego Saenz de Urturi
- Department of Physiology Faculty of Medicine and Nursing University of Basque Country UPV/EHU Leioa Spain
| | - Maitane Nuñez‐García
- Department of Physiology Faculty of Medicine and Nursing University of Basque Country UPV/EHU Leioa Spain
| | - Francisco Gonzalez‐Romero
- Department of Physiology Faculty of Medicine and Nursing University of Basque Country UPV/EHU Leioa Spain
| | - Xabier Buque
- Department of Physiology Faculty of Medicine and Nursing University of Basque Country UPV/EHU Leioa Spain
- Biocruces Bizkaia Health Research Institute Cruces University Hospital Barakaldo Spain
| | - Igor Aurrekoetxea
- Department of Physiology Faculty of Medicine and Nursing University of Basque Country UPV/EHU Leioa Spain
- Biocruces Bizkaia Health Research Institute Cruces University Hospital Barakaldo Spain
| | - Virginia Gutiérrez de Juan
- Liver Disease Lab, Center for Cooperative Research in Bioscience (CIC bioGUNE), Basque Research and Technology Alliance (BRTA) e Derio Bizkaia Spain
| | - Maria J. Gonzalez‐Rellan
- Department of Physiology CIMUS University of Santiago de Compostela‐Instituto de Investigación Sanitaria Santiago de Compostela Spain
- CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn) Madrid Spain
| | - Carmelo García‐Monzón
- Liver Research Unit Santa Cristina University Hospital Instituto de Investigación Sanitaria Princesa Madrid Spain
- Centro de investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Carlos III National Health Institute Madrid Spain
| | - Águeda González‐Rodríguez
- Liver Research Unit Santa Cristina University Hospital Instituto de Investigación Sanitaria Princesa Madrid Spain
- Centro de investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Carlos III National Health Institute Madrid Spain
| | - Lorena Mosteiro
- Biocruces Bizkaia Health Research Institute Cruces University Hospital Barakaldo Spain
| | - Gaizka Errazti
- Biocruces Bizkaia Health Research Institute Cruces University Hospital Barakaldo Spain
| | - Patricia Mifsut
- Biocruces Bizkaia Health Research Institute Cruces University Hospital Barakaldo Spain
| | - Sonia Gaztambide
- Biocruces Bizkaia Health Research Institute Cruces University Hospital Barakaldo Spain
| | - Luis Castaño
- Biocruces Bizkaia Health Research Institute Cruces University Hospital Barakaldo Spain
| | - Cesar Martin
- Department of Biochemistry and Molecular Biology Biofisika Institute (UPV/EHU, CSIC) UPV/EHU Spain
| | - Rubén Nogueiras
- Department of Physiology CIMUS University of Santiago de Compostela‐Instituto de Investigación Sanitaria Santiago de Compostela Spain
- CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn) Madrid Spain
| | - María L. Martinez‐Chantar
- Liver Disease Lab, Center for Cooperative Research in Bioscience (CIC bioGUNE), Basque Research and Technology Alliance (BRTA) e Derio Bizkaia Spain
- Centro de investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Carlos III National Health Institute Madrid Spain
| | - Wing‐Kin Syn
- Department of Physiology Faculty of Medicine and Nursing University of Basque Country UPV/EHU Leioa Spain
- Section of Gastroenterology Ralph H Johnson VAMC Charleston SC USA
- Division of Gastroenterology and Hepatology Medical University of South Carolina Charleston SC USA
| | - Patricia Aspichueta
- Department of Physiology Faculty of Medicine and Nursing University of Basque Country UPV/EHU Leioa Spain
- Biocruces Bizkaia Health Research Institute Cruces University Hospital Barakaldo Spain
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34
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Ganoderic acid A attenuates high-fat-diet-induced liver injury in rats by regulating the lipid oxidation and liver inflammation. Arch Pharm Res 2020; 43:744-754. [PMID: 32715385 DOI: 10.1007/s12272-020-01256-9] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2020] [Accepted: 07/24/2020] [Indexed: 01/04/2023]
Abstract
Ganoderic Acid A (GA) has many pharmacological effects such as anti-tumor, antibacterial, anti-inflammatory, and immunosuppressive effects. However, the protective effect of GA on liver injury has not been reported. This study aimed to investigate the action of GA on insufficient methionine and choline combined with high-fat diet (HFD)-induced non-alcoholic fatty liver disease (NAFLD) in rats. NAFLD model was established by insufficient methionine and choline combined with high fat feeding to rats. The levels of Acetyl-CoA carboxylase, fatty acid synthase, sterol regulatory element binding protein, liver X receptors, AMP-activated protein kinase, peroxisome proliferator-activated receptor α, PPARg coactivator 1α and NF-κB pathway in the liver were detected by western blot. The results of this study demonstrated that the expression of GA can not only significantly decrease the live weight and liver weight per body weight of HFD mice, but also restore the alanine aminotransferase, aspartate aminotransferase, total bilirubin levels, triglyceride and cholesterol in serum. In addition, the expression of GA increased the levels of high-density lipoprotein cholesterol in serum, ameliorated pathological changes and decreased NAS score of mice's liver. In conclusion, the treatment with GA could improve NAFLD in rats by regulating the levels of signaling events involved in free fatty acid production, lipid oxidation and liver inflammation.
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35
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de Conti A, Tryndyak V, Willett RA, Borowa-Mazgaj B, Watson A, Patton R, Khare S, Muskhelishvili L, Olson GR, Avigan MI, Cerniglia CE, Ross SA, Sanyal AJ, Beland FA, Rusyn I, Pogribny IP. Characterization of the variability in the extent of nonalcoholic fatty liver induced by a high-fat diet in the genetically diverse Collaborative Cross mouse model. FASEB J 2020; 34:7773-7785. [PMID: 32304142 DOI: 10.1096/fj.202000194r] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2020] [Revised: 03/24/2020] [Accepted: 03/25/2020] [Indexed: 02/06/2023]
Abstract
Interindividual variability and sexual dimorphisms in the development of nonalcoholic fatty liver disease (NAFLD) are still poorly understood. In the present study, male and female strains of Collaborative Cross (CC) mice were fed a high-fat and high-sucrose (HF/HS) diet or a control diet for 12 weeks to investigate interindividual- and sex-specific variations in the development of NAFLD. The severity of liver steatosis varied between sexes and individual strains and was accompanied by an elevation of serum markers of insulin resistance, including increases in total cholesterol, low-density lipoproteins, high-density lipoproteins, phospholipids, and glucose. The development of NAFLD was associated with overexpression of the critical fatty acid uptake and de novo lipogenesis genes Pparg, Mogat1, Cd36, Acaab1, Fabp2, and Gdf15 in male and female mice. The expression of Pparg, Mogat1, and Cd36 was positively correlated with liver triglycerides in male mice, and Mogat1 and Cd36 expression were positively correlated with liver triglycerides in female mice. Our results indicate the value of CC mice in combination with HF/HS diet-induced alterations as an approach to study the susceptibility and interindividual variabilities in the pathogenesis of nonalcoholic fatty liver and early nonalcoholic steatohepatitis at the population level, uncovering of susceptible and resistant cohorts, and identifying sex-specific molecular determinants of disease susceptibility.
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Affiliation(s)
- Aline de Conti
- Division of Biochemical Toxicology, FDA-National Center for Toxicological Research, Jefferson, AR, USA
| | - Volodymyr Tryndyak
- Division of Biochemical Toxicology, FDA-National Center for Toxicological Research, Jefferson, AR, USA
| | - Rose A Willett
- Division of Biochemical Toxicology, FDA-National Center for Toxicological Research, Jefferson, AR, USA
| | - Barbara Borowa-Mazgaj
- Division of Biochemical Toxicology, FDA-National Center for Toxicological Research, Jefferson, AR, USA
| | - Anna Watson
- Division of Biochemical Toxicology, FDA-National Center for Toxicological Research, Jefferson, AR, USA
| | - Ralph Patton
- Toxicologic Pathology Associates, Jefferson, AR, USA
| | - Sangeeta Khare
- Division of Microbiology, FDA-National Center for Toxicological Research, Jefferson, AR, USA
| | | | - Greg R Olson
- Toxicologic Pathology Associates, Jefferson, AR, USA
| | - Mark I Avigan
- Office of Pharmacovigilance and Epidemiology, FDA-Center for Drug Evaluation and Research, Silver Spring, MD, USA
| | - Carl E Cerniglia
- Division of Microbiology, FDA-National Center for Toxicological Research, Jefferson, AR, USA
| | - Sharon A Ross
- Division of Cancer Prevention, National Cancer Institute, Bethesda, MD, USA
| | - Arun J Sanyal
- Department of Internal Medicine, Virginia Commonwealth University, Richmond, VA, USA
| | - Frederick A Beland
- Division of Biochemical Toxicology, FDA-National Center for Toxicological Research, Jefferson, AR, USA
| | - Ivan Rusyn
- Department of Veterinary Integrative Biosciences, Texas A&M University, College Station, TX, USA
| | - Igor P Pogribny
- Division of Biochemical Toxicology, FDA-National Center for Toxicological Research, Jefferson, AR, USA
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36
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Santinha D, Klopot A, Marques I, Ellis E, Jorns C, Johansson H, Melo T, Antonson P, Jakobsson T, Félix V, Gustafsson JÅ, Domingues MR, Mode A, Helguero LA. Lipidomic analysis of human primary hepatocytes following LXR activation with GW3965 identifies AGXT2L1 as a main target associated to changes in phosphatidylethanolamine. J Steroid Biochem Mol Biol 2020; 198:105558. [PMID: 31783151 DOI: 10.1016/j.jsbmb.2019.105558] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/22/2019] [Revised: 11/25/2019] [Accepted: 11/26/2019] [Indexed: 02/06/2023]
Abstract
Liver X receptor (LXR) agonists have the potential to alleviate obesity related diseases, particularly atherosclerosis. However, LXRs are transcriptional regulators that induce de novo lipogenesis and lipid accumulation in hepatocytes which represents a serious adverse effect. In this work, we sought to characterize the LXR agonist GW3965 effects on fatty acid (FA) and phospholipid (PL) remodelling and the correlation with gene expression in order to better understand the underlying effects leading to hepatic pathology upon LXR activation. Human primary hepatocytes treated for 48 h with GW3965 were analysed for changes in lipid metabolism gene expression by qPCR, variations in the FA profile was evaluated by GC-FID and in PL profiles using thin layer chromatography, ESI-MS and MS/MS analysis. Changes in cell membrane biochemical properties were studied using bilayer models generated with CHARMM-GUI. ELOLV6 and SCD1 mRNA increase was consistent with higher C16:1 and C18:1n9 at the expense of C16:0 and C18:0. The reduction of C18:2n6 and increase in C20:2n6 was in agreement with ELOVL5 upregulation. Phosphatydilethanolamine (PE) levels tended to decrease and phosphatidylinositol to increase; although differences did not reach significance, they correlated with changes in AGXT2L1, CDS1 and LPIN1 mRNA levels that were increased. The overall effect of GW3965 on PEs molecular profiles was an increase of long-chain polyunsaturated FA chains and a decrease of C16/C18 saturated and monounsaturated FAs chains. Additionally, PC (32:1) and PC (34:2) were decreased, and PC (36:1) and PC (34:1) were increased. AGXT2L1 is an enzyme with strict substrate specificity for phosphoethanolamine, which is converted into ammonia in GW3965-treated hepatocytes and could explain the PE reduction. In summary, LXR activation by GW3965 targets PE biosynthesis and FA elongation/desaturation, which tends to decrease PE in relation to total PL levels, and remodelling of PC and PE molecular species. We identified the human AGXT2L1 gene as induced by LXR activation by both synthetic and endogenous agonist treatment. The increase in acetaldehyde-induced oxidative stress, and in the lipid species identified have the potential to enhance the inflammatory process and impair membrane function. Future studies should focus on inhibition of AGXT2L1 activity with the aim of reverting the steatosis induced by LXR activation.
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Affiliation(s)
- Deolinda Santinha
- Department of Chemistry, QOPNA Research Unit, University of Aveiro, Portugal
| | - Anna Klopot
- Department of Biosciences and Nutrition, Karolinska Institutet, Neo, Huddinge, Sweden
| | - Igor Marques
- Department of Chemistry, CICECO - Aveiro Institute of Materials, University of Aveiro, 3810-193 Aveiro, Portugal
| | - Ewa Ellis
- Department of Clinical Science, Intervention and Technology (CLINTEC), Division of Transplantation Surgery, Unit for Liver Transplantation, Karolinska University Hospital Huddinge, Stockholm, Sweden
| | - Carl Jorns
- Department of Clinical Science, Intervention and Technology (CLINTEC), Division of Transplantation Surgery, Unit for Liver Transplantation, Karolinska University Hospital Huddinge, Stockholm, Sweden
| | - Helene Johansson
- Department of Clinical Science, Intervention and Technology (CLINTEC), Division of Transplantation Surgery, Unit for Liver Transplantation, Karolinska University Hospital Huddinge, Stockholm, Sweden
| | - Tânia Melo
- Department of Chemistry, QOPNA Research Unit, University of Aveiro, Portugal; Department of Chemistry, CESAM&ECOMARE, University of Aveiro, 3810-193 Aveiro, Portugal
| | - Per Antonson
- Department of Biosciences and Nutrition, Karolinska Institutet, Neo, Huddinge, Sweden
| | - Tomas Jakobsson
- Department of Laboratory Medicine, Karolinska Institutet, Huddinge, Sweden
| | - Vítor Félix
- Department of Chemistry, CICECO - Aveiro Institute of Materials, University of Aveiro, 3810-193 Aveiro, Portugal
| | - Jan-Åke Gustafsson
- Department of Biosciences and Nutrition, Karolinska Institutet, Neo, Huddinge, Sweden; Center for Nuclear Receptors and Cell Signaling, Department of Cell Biology and Biochemistry, University of Houston, TX, United States
| | - Maria Rosário Domingues
- Department of Chemistry, QOPNA Research Unit, University of Aveiro, Portugal; Department of Chemistry, CESAM&ECOMARE, University of Aveiro, 3810-193 Aveiro, Portugal
| | - Agneta Mode
- Department of Biosciences and Nutrition, Karolinska Institutet, Neo, Huddinge, Sweden
| | - Luisa A Helguero
- Department of Medical Sciences, iBiMED - Institute of Biomedicine, University of Aveiro, 3810-193 Aveiro, Portugal.
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37
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Becares N, Gage MC, Voisin M, Shrestha E, Martin-Gutierrez L, Liang N, Louie R, Pourcet B, Pello OM, Luong TV, Goñi S, Pichardo-Almarza C, Røberg-Larsen H, Diaz-Zuccarini V, Steffensen KR, O'Brien A, Garabedian MJ, Rombouts K, Treuter E, Pineda-Torra I. Impaired LXRα Phosphorylation Attenuates Progression of Fatty Liver Disease. Cell Rep 2020; 26:984-995.e6. [PMID: 30673619 PMCID: PMC6344342 DOI: 10.1016/j.celrep.2018.12.094] [Citation(s) in RCA: 49] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2018] [Revised: 11/01/2018] [Accepted: 12/20/2018] [Indexed: 01/21/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a very common indication for liver transplantation. How fat-rich diets promote progression from fatty liver to more damaging inflammatory and fibrotic stages is poorly understood. Here, we show that disrupting phosphorylation at Ser196 (S196A) in the liver X receptor alpha (LXRα, NR1H3) retards NAFLD progression in mice on a high-fat-high-cholesterol diet. Mechanistically, this is explained by key histone acetylation (H3K27) and transcriptional changes in pro-fibrotic and pro-inflammatory genes. Furthermore, S196A-LXRα expression reveals the regulation of novel diet-specific LXRα-responsive genes, including the induction of Ces1f, implicated in the breakdown of hepatic lipids. This involves induced H3K27 acetylation and altered LXR and TBLR1 cofactor occupancy at the Ces1f gene in S196A fatty livers. Overall, impaired Ser196-LXRα phosphorylation acts as a novel nutritional molecular sensor that profoundly alters the hepatic H3K27 acetylome and transcriptome during NAFLD progression placing LXRα phosphorylation as an alternative anti-inflammatory or anti-fibrotic therapeutic target.
LXRαS196A induces liver steatosis and prevents cholesterol accumulation LXRαS196A reduces progression to hepatic inflammation and fibrosis LXRαS196A modulates hepatic chromatin acetylation LXRαS196A reveals unique dual LXRα phosphorylation and diet-responsive genes
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Affiliation(s)
- Natalia Becares
- Centre of Cardiometabolic Medicine, Division of Medicine, University College of London, London WC1 E6JF, UK
| | - Matthew C Gage
- Centre of Cardiometabolic Medicine, Division of Medicine, University College of London, London WC1 E6JF, UK
| | - Maud Voisin
- Department of Microbiology, New York University School of Medicine, New York, NY 10016, USA
| | - Elina Shrestha
- Department of Microbiology, New York University School of Medicine, New York, NY 10016, USA
| | - Lucia Martin-Gutierrez
- Centre of Cardiometabolic Medicine, Division of Medicine, University College of London, London WC1 E6JF, UK
| | - Ning Liang
- Karolinska Institute, Centre for Innovative Medicine (CIMED), Department of Biosciences and Nutrition, 14183 Huddinge, Sweden
| | - Rikah Louie
- Centre of Cardiometabolic Medicine, Division of Medicine, University College of London, London WC1 E6JF, UK
| | - Benoit Pourcet
- Centre of Cardiometabolic Medicine, Division of Medicine, University College of London, London WC1 E6JF, UK
| | - Oscar M Pello
- Centre of Cardiometabolic Medicine, Division of Medicine, University College of London, London WC1 E6JF, UK
| | - Tu Vinh Luong
- Department of Cellular Pathology, Royal Free London NHS Foundation Trust, London NW3 2QG, UK
| | - Saioa Goñi
- Department of Microbiology, New York University School of Medicine, New York, NY 10016, USA
| | | | | | | | - Knut R Steffensen
- Division of Clinical Chemistry, Department of Laboratory Medicine, Karolinska Institute, 14186 Huddinge, Sweden
| | - Alastair O'Brien
- Centre of Cardiometabolic Medicine, Division of Medicine, University College of London, London WC1 E6JF, UK
| | - Michael J Garabedian
- Department of Microbiology, New York University School of Medicine, New York, NY 10016, USA
| | - Krista Rombouts
- Institute for Liver & Digestive Health, University College London, Royal Free, London NW3 2PF, UK
| | - Eckardt Treuter
- Karolinska Institute, Centre for Innovative Medicine (CIMED), Department of Biosciences and Nutrition, 14183 Huddinge, Sweden
| | - Inés Pineda-Torra
- Centre of Cardiometabolic Medicine, Division of Medicine, University College of London, London WC1 E6JF, UK.
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Hodson L, Gunn PJ. The regulation of hepatic fatty acid synthesis and partitioning: the effect of nutritional state. Nat Rev Endocrinol 2019; 15:689-700. [PMID: 31554932 DOI: 10.1038/s41574-019-0256-9] [Citation(s) in RCA: 178] [Impact Index Per Article: 29.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is an increasing global public health burden. NAFLD is strongly associated with type 2 diabetes mellitus, obesity and cardiovascular disease and begins with intrahepatic triacylglycerol accumulation. Under healthy conditions, the liver regulates lipid metabolism to meet systemic energy needs in the fed and fasted states. The processes of fatty acid uptake, fatty acid synthesis and the intracellular partitioning of fatty acids into storage, oxidation and secretion pathways are tightly regulated. When one or more of these processes becomes dysregulated, excess lipid accumulation can occur. Although genetic and environmental factors have been implicated in the development of NAFLD, it remains unclear why an imbalance in these pathways begins. The regulation of fatty acid partitioning occurs at several points, including during triacylglycerol synthesis, lipid droplet formation and lipolysis. These processes are influenced by enzyme function, intake of dietary fats and sugars and whole-body metabolism, and are further affected by the presence of obesity or insulin resistance. Insight into how the liver controls fatty acid metabolism in health and how these processes might be affected in disease would offer the potential for new therapeutic treatments for NAFLD to be developed.
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Affiliation(s)
- Leanne Hodson
- Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Headington, Oxford, UK.
- Oxford NIHR Biomedical Research Centre, Churchill Hospital, Headington, Oxford, UK.
| | - Pippa J Gunn
- Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Headington, Oxford, UK
- Oxford NIHR Biomedical Research Centre, Churchill Hospital, Headington, Oxford, UK
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Hodson L, Karpe F. Hyperinsulinaemia: does it tip the balance toward intrahepatic fat accumulation? Endocr Connect 2019; 8:R157-R168. [PMID: 31581129 PMCID: PMC6826170 DOI: 10.1530/ec-19-0350] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/24/2019] [Accepted: 09/26/2019] [Indexed: 12/12/2022]
Abstract
In health, the liver is metabolically flexible over the course of the day, as it undertakes a multitude of physiological processes including the regulation of intrahepatic and systemic glucose and lipid levels. The liver is the first organ to receive insulin and through a cascade of complex metabolic processes, insulin not only plays a key role in the intrahepatic regulation of glucose and lipid metabolism, but also in the regulation of systemic glucose and lipid concentrations. Thus, when intrahepatic insulin signalling becomes aberrant then this may lead to perturbations in intrahepatic metabolic processes that have the potential to impact on metabolic health. For example, obesity is associated with intrahepatic fat accumulation (known as nonalcoholic liver disease (NAFLD)) and hyperinsulinaemia, the latter as a result of insulin hypersecretion or impaired hepatic insulin extraction. Although insulin signalling directly alters intra- and extrahepatic metabolism, the regulation of hepatic glucose and fatty acid metabolism is also indirectly driven by substrate availability. Here we discuss the direct and indirect effects of insulin on intrahepatic processes such as the synthesis of fatty acids and peripherally regulating the flux of fatty acids to the liver; processes that may play a role in the development of insulin resistance and/or intrahepatocellular triacylglycerol (IHTAG) accumulation in humans.
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Affiliation(s)
- Leanne Hodson
- Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford and National Institute for Health Research (NIHR) Oxford Biomedical Research Centre (BRC), Oxford University Hospital Trusts, Oxford, UK
| | - Fredrik Karpe
- Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford and National Institute for Health Research (NIHR) Oxford Biomedical Research Centre (BRC), Oxford University Hospital Trusts, Oxford, UK
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40
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Abstract
Nonalcoholic fatty liver disease (NAFLD) was first described as a distinct clinical entity four decades ago. However, the condition has become the centre of attention within hepatology owing to its high prevalence and growing contribution to the burden of end-stage liver disease in the general population. This Perspective provides an overview on the development of knowledge related to NAFLD with a focus on landmark findings that have influenced current paradigms and key knowledge gaps that need to be filled to make progress. Specifically, a timeline of scientific discovery of both basic disease mechanisms (with a focus on human data) and the evolution of knowledge about the clinical course of the disease is provided and related to current approaches to treat and eventually prevent NAFLD.
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Affiliation(s)
- Arun J Sanyal
- Division of Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University, School of Medicine, Richmond, VA, USA.
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41
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Ni M, Zhang B, Zhao J, Feng Q, Peng J, Hu Y, Zhao Y. Biological mechanisms and related natural modulators of liver X receptor in nonalcoholic fatty liver disease. Biomed Pharmacother 2019; 113:108778. [PMID: 30897538 DOI: 10.1016/j.biopha.2019.108778] [Citation(s) in RCA: 34] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2019] [Revised: 03/11/2019] [Accepted: 03/13/2019] [Indexed: 02/07/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is becoming a worldwide health problem, but no approved medical treatment exists so far. Nuclear receptors are one of the drug targets for nonalcoholic steatohepatitis (NASH). Among them, liver X receptor (LXR) has been studied in recent years in tumors, metabolic diseases and inflammatory diseases, but its physiological and pharmacological effects in the treatment of NASH are controversial. Activation of LXR has the potential to modulate cholesterol homeostasis, induce anti-inflammatory effects and increase insulin sensitivity, but liver lipid deposition and hypertriglyceridemia are also increased. Inhibition of liver LXR transcriptional activity in the context of NAFLD can effectively alleviate hepatic steatosis, inflammation, and fibrosis but elevates the risk of potential cardiovascular disease. The contradictory pharmacodynamic effects of LXR in the treatment of NASH increase the difficulty of developing targeted drugs. Moreover, natural compounds play an important part in drug development, and in recent years, some natural compounds have been reported to treat NAFLD by acting on LXR or LXR pathways with fewer adverse reactions, presenting a promising therapeutic prospect. In this review, we discuss the mechanisms of LXR in NASH and summarize the natural products reported to modulate NAFLD via LXR or the LXR pathway, offering an alternative approach for LXR-related drug development in NAFLD.
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Affiliation(s)
- Mingzhu Ni
- Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Institute of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Binbin Zhang
- Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Institute of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Jianan Zhao
- Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Institute of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Qin Feng
- Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Institute of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China; Shanghai Key laboratory of Traditional Chinese Medicine, Shanghai 201203, China
| | - Jinghua Peng
- Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Institute of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China; Shanghai Key laboratory of Traditional Chinese Medicine, Shanghai 201203, China
| | - Yiyang Hu
- Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Institute of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China; Shanghai Key laboratory of Traditional Chinese Medicine, Shanghai 201203, China; E-Institute of Shanghai Municipal Education Commission, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
| | - Yu Zhao
- Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Institute of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China; Shanghai Key laboratory of Traditional Chinese Medicine, Shanghai 201203, China.
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42
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High-fat diet alters PAS kinase regulation by fasting and feeding in liver. J Nutr Biochem 2018; 57:14-25. [DOI: 10.1016/j.jnutbio.2018.03.003] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2017] [Revised: 01/19/2018] [Accepted: 03/01/2018] [Indexed: 12/12/2022]
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43
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Hwang JT, Shin EJ, Chung MY, Park JH, Chung S, Choi HK. Ethanol extract of Allium fistulosum inhibits development of non-alcoholic fatty liver disease. Nutr Res Pract 2018; 12:110-117. [PMID: 29629027 PMCID: PMC5886962 DOI: 10.4162/nrp.2018.12.2.110] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2017] [Revised: 11/17/2017] [Accepted: 02/21/2018] [Indexed: 12/25/2022] Open
Abstract
BACKGROUND/OBJECTIVES Non-alcoholic fatty liver disease (NAFLD) is a leading cause of chronic liver disease and is closely associated with metabolic syndrome. In the present study, we observed the effect of ethanol extract of Allium fistulosum (EAF) on NAFLD and have suggested the possibility of using EAF as a natural product for application in the development of a treatment for NAFLD. MATERIALS/METHODS The preventive effect on hepatic lipid accumulation was estimated by using an oleic acid (OA)-induced NAFLD model in vitro and a Western diet (high-fat high-sucrose; WD)-induced obese mouse model. Animals were divided into three groups (n = 7): normal diet group (ND), WD group, and WD plus 1% EAF group. RESULTS EAF reduced OA-stimulated lipid accumulation in HepG2 cells in the absence of cellular cytotoxicity and significantly blocked transcriptional activation of sterol regulatory element-binding protein 1 and fatty acid synthase genes. Subsequently, we investigated these effects in vivo in mice fed either ND or WD in the presence or absence of EAF supplementation. In comparison to the ND controls, the WD-fed mice exhibited increases in body weight, liver weight, epididymal fat weight, and accumulation of fat in hepatocytes, and these effects were significantly attenuated by EAF supplementation. CONCLUSIONS Allium fistulosum attenuates the development of NAFLD, and EAF elicits anti-lipogenic activity in liver. Therefore, EAF represents a promising candidate for use in the development of novel therapeutic drugs or drug combinations for the prevention and treatment of NAFLD.
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Affiliation(s)
- Jin-Taek Hwang
- Korea Food Research Institute, 245 Nongsaengmyeong-ro, Jeonbuk 55365, Korea.,Department of Food Biotechnology, Korea University of Science & Technology, Daejeon 34113, Korea
| | - Eun Ju Shin
- Korea Food Research Institute, 245 Nongsaengmyeong-ro, Jeonbuk 55365, Korea.,Department of Food Biotechnology, Korea University of Science & Technology, Daejeon 34113, Korea
| | - Min-Yu Chung
- Korea Food Research Institute, 245 Nongsaengmyeong-ro, Jeonbuk 55365, Korea
| | - Jae Ho Park
- Korea Food Research Institute, 245 Nongsaengmyeong-ro, Jeonbuk 55365, Korea.,Department of Food Biotechnology, Korea University of Science & Technology, Daejeon 34113, Korea
| | - Sangwon Chung
- Korea Food Research Institute, 245 Nongsaengmyeong-ro, Jeonbuk 55365, Korea
| | - Hyo-Kyoung Choi
- Korea Food Research Institute, 245 Nongsaengmyeong-ro, Jeonbuk 55365, Korea
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Zheng J, Li Z, Manabe Y, Kim M, Goto T, Kawada T, Sugawara T. Siphonaxanthin, a Carotenoid From Green Algae, Inhibits Lipogenesis in Hepatocytes via the Suppression of Liver X Receptor α Activity. Lipids 2018; 53:41-52. [PMID: 29446839 DOI: 10.1002/lipd.12002] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2017] [Revised: 09/20/2017] [Accepted: 10/17/2017] [Indexed: 12/14/2022]
Abstract
Nonalcoholic fatty liver disease (NAFLD) has shown an increasing morbidity in recent years. Here, we demonstrated that siphonaxanthin (SPX), a rare marine carotenoid, exhibits a strong inhibitory effect on aggravated hepatic lipogenesis in vitro and would be a promising candidate in the prevention and alleviation of NAFLD in the future. In this study, we conducted a preliminary assessment of the effect of SPX on hepatic lipogenesis by using the HepG2 cell line, derived from human liver cancer, as a model of the liver. SPX significantly suppressed the excess accumulation of triacylglycerol induced by liver X receptor α (LXRα) agonist by downregulating a nuclear transcription factor named sterol regulatory element-binding protein-1c and a set of related genes. Moreover, fatty acid translocase (CD36) and fatty acid-binding protein-1, which regulates fatty acid uptake, also exhibited significant decrease in transcriptional levels. Furthermore, we found that SPX blocked LXRα activation and would be a promising candidate for antagonist of LXRα.
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Affiliation(s)
- Jiawen Zheng
- Division of Applied Biosciences, Graduate School of Agriculture, Kyoto University, Kyoto, 606-8502, Japan
| | - Zhuosi Li
- Division of Applied Biosciences, Graduate School of Agriculture, Kyoto University, Kyoto, 606-8502, Japan
| | - Yuki Manabe
- Division of Applied Biosciences, Graduate School of Agriculture, Kyoto University, Kyoto, 606-8502, Japan
| | - Minji Kim
- Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Kyoto, 611-0011, Japan
| | - Tsuyoshi Goto
- Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Kyoto, 611-0011, Japan
| | - Teruo Kawada
- Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Kyoto, 611-0011, Japan
| | - Tatsuya Sugawara
- Division of Applied Biosciences, Graduate School of Agriculture, Kyoto University, Kyoto, 606-8502, Japan
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45
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Lin YM, Sun HY, Chiu WT, Su HC, Chien YC, Chong LW, Chang HC, Bai CH, Young KC, Tsao CW. Calcitriol Inhibits HCV Infection via Blockade of Activation of PPAR and Interference with Endoplasmic Reticulum-Associated Degradation. Viruses 2018; 10:v10020057. [PMID: 29385741 PMCID: PMC5850364 DOI: 10.3390/v10020057] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2017] [Revised: 01/17/2018] [Accepted: 01/26/2018] [Indexed: 02/06/2023] Open
Abstract
Vitamin D has been identified as an innate anti-hepatitis C virus (HCV) agent but the possible mechanisms for this issue remain unclear. Here, we clarified the mechanisms of calcitriol-mediated inhibition of HCV infection. Calcitriol partially inhibited HCV infection, nitric oxide (NO) release and lipid accumulation in Huh7.5 human hepatoma cells via the activation of vitamin D receptor (VDR). When cells were pretreated with the activators of peroxisome proliferator-activated receptor (PPAR)-α (Wy14643) and -γ (Ly171883), the calcitriol-mediated HCV suppression was reversed. Otherwise, three individual stimulators of PPAR-α/β/γ blocked the activation of VDR. PPAR-β (linoleic acid) reversed the inhibition of NO release, whereas PPAR-γ (Ly171883) reversed the inhibitions of NO release and lipid accumulation in the presence of calcitriol. The calcitriol-mediated viral suppression, inhibition of NO release and activation of VDR were partially blocked by an inhibitor of endoplasmic reticulum-associated degradation (ERAD), kifunensine. Furthermore, calcitriol blocked the HCV-induced expressions of apolipoprotein J and 78 kDa glucose-regulated protein, which was restored by pretreatment of kifunensine. These results indicated that the calcitriol-mediated HCV suppression was associated with the activation of VDR, interference with ERAD process, as well as blockades of PPAR, lipid accumulation and nitrative stress.
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Affiliation(s)
- Yu-Min Lin
- Department of Gastroenterology, Shin Kong Wu Ho-Su Memorial Hospital, Taipei 11101, Taiwan.
| | - Hung-Yu Sun
- Department of Medical Laboratory Science and Biotechnology, College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan.
| | - Wen-Tai Chiu
- Department of Biomedical Engineering, College of Engineering, National Cheng Kung University, Tainan 70101, Taiwan.
| | - Hui-Chen Su
- Department of Pharmacy, Chi-Mei Medical Center, Tainan 71004, Taiwan.
| | - Yu-Chieh Chien
- Department of Medical Laboratory Science and Biotechnology, College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan.
- Department of Long Term Care, Chung Hwa University of Medical Technology, Tainan 71703, Taiwan.
| | - Lee-Won Chong
- Department of Gastroenterology, Shin Kong Wu Ho-Su Memorial Hospital, Taipei 11101, Taiwan.
| | - Hung-Chuen Chang
- Department of Gastroenterology, Shin Kong Wu Ho-Su Memorial Hospital, Taipei 11101, Taiwan.
| | - Chyi-Huey Bai
- Department of Public Health, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan.
| | - Kung-Chia Young
- Department of Medical Laboratory Science and Biotechnology, College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan.
| | - Chiung-Wen Tsao
- Department of Long Term Care, Chung Hwa University of Medical Technology, Tainan 71703, Taiwan.
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Liu Z, Nahon P, Li Z, Yin P, Li Y, Amathieu R, Ganne-Carrié N, Ziol M, Sellier N, Seror O, Le Moyec L, Savarin P, Xu G. Determination of candidate metabolite biomarkers associated with recurrence of HCV-related hepatocellular carcinoma. Oncotarget 2018; 9:6245-6258. [PMID: 29464069 PMCID: PMC5814209 DOI: 10.18632/oncotarget.23500] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2017] [Accepted: 10/05/2017] [Indexed: 02/07/2023] Open
Abstract
Hepatitis C virus (HCV) infection is associated with a high risk of developing hepatocellular carcinoma (HCC) and HCC recurrence remains the primary threat to outcomes after curative therapy. In this study, we compared recurrent and non-recurrent HCC patients treated with radiofrequency ablation (RFA) in order to identify characteristic metabolic profile variations associated with HCC recurrence. Gas chromatography-mass spectrometry (GC-MS) -based metabolomic analyses were conducted on serum samples obtained before and after RFA therapy. Significant variations were observed in metabolites in the glycerolipid, tricarboxylic acid (TCA) cycle, fatty acid, and amino acid pathways between recurrent and non-recurrent patients. Observed differences in metabolites associated with recurrence did not coincide before and after treatment except for fatty acids. Based on the comparison of serum metabolomes between recurrent and non-recurrent patients, key discriminatory metabolites were defined by a random forest (RF) test. Two combinations of these metabolites before and after RFA treatment showed outstanding performance in predicting HCV-related HCC recurrence, they were further confirmed by an external validation set. Our study showed that the determined combination of metabolites may be potential biomarkers for the prediction of HCC recurrence before and after RFA treatment.
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Affiliation(s)
- Zhicheng Liu
- CAS Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, China
- Université Paris 13, Sorbonne Paris Cité, Laboratoire de Chimie, Structures et Propriétés de Biomateriaux et d’Agents Therapeutiques, UMR 7244, Bobigny, France
| | - Pierre Nahon
- Hepatology Unit, Jean Verdier Teaching Hospital, AP-HP, Bondy, France
- INSERM U1162, Génomique Fonctionnelle des Tumeurs Solides, INSERM U1162, Paris, France
- University Paris 13, Bobigny, France
| | - Zaifang Li
- CAS Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, China
| | - Peiyuan Yin
- CAS Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, China
| | - Yanli Li
- CAS Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, China
| | - Roland Amathieu
- Université Paris 13, Sorbonne Paris Cité, Laboratoire de Chimie, Structures et Propriétés de Biomateriaux et d’Agents Therapeutiques, UMR 7244, Bobigny, France
- Intensive Care Unit, Jean Verdier Teaching Hospital, AP-HP, Bondy, France
| | - Nathalie Ganne-Carrié
- Hepatology Unit, Jean Verdier Teaching Hospital, AP-HP, Bondy, France
- University Paris 13, Bobigny, France
| | - Marianne Ziol
- APHP, Service d'Anatomie Pathologique, Hôpital Jean Verdier, BB-0033-00027, Centre de Ressources Biologiques Maladies du foie, Groupe Hospitalier, Paris-Seine-Saint-Denis, France
- BB-0033-00027, Centre de Ressources Biologiques Maladies du Foie, Groupe Hospitalier Paris-Seine-Saint-Denis, Bondy, France
| | - Nicolas Sellier
- APHP, Service de Radiologie, Hôpital Jean Verdier, Bondy, France
| | - Olivier Seror
- INSERM U1162, Génomique Fonctionnelle des Tumeurs Solides, INSERM U1162, Paris, France
- APHP, Service de Radiologie, Hôpital Jean Verdier, Bondy, France
| | | | - Philippe Savarin
- Université Paris 13, Sorbonne Paris Cité, Laboratoire de Chimie, Structures et Propriétés de Biomateriaux et d’Agents Therapeutiques, UMR 7244, Bobigny, France
| | - Guowang Xu
- CAS Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, China
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47
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Kumei S, Yuhki KI, Kojima F, Kashiwagi H, Imamichi Y, Okumura T, Narumiya S, Ushikubi F. Prostaglandin I 2 suppresses the development of diet-induced nonalcoholic steatohepatitis in mice. FASEB J 2017; 32:2354-2365. [PMID: 29247122 DOI: 10.1096/fj.201700590r] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
Nonalcoholic steatohepatitis (NASH) is a hepatic manifestation of metabolic syndrome. Although the prostaglandin (PG)I2 receptor IP is expressed broadly in the liver, the role of PGI2-IP signaling in the development of NASH remains to be determined. Here, we investigated the role of the PGI2-IP system in the development of steatohepatitis using mice lacking the PGI2 receptor IP [IP-knockout (IP-KO) mice] and beraprost (BPS), a specific IP agonist. IP-KO and wild-type (WT) mice were fed a methionine- and choline-deficient diet (MCDD) for 2, 5, or 10 wk. BPS was administered orally to mice every day during the experimental periods. The effect of BPS on the expression of chemokine and inflammatory cytokines was examined also in cultured Kupffer cells. WT mice fed MCDD developed steatohepatitis at 10 wk. IP-KO mice developed steatohepatitis at 5 wk with augmented histologic derangements accompanied by increased hepatic monocyte chemoattractant protein-1 (MCP-1) and TNF-α concentrations. After 10 wk of MCDD, IP-KO mice had greater hepatic iron deposition with prominent oxidative stress, resulting in hepatocyte damage. In WT mice, BPS improved histologic and biochemical parameters of steatohepatitis, accompanied by reduced hepatic concentration of MCP-1 and TNF-α. Accordingly, BPS suppressed the LPS-stimulated Mcp-1 and Tnf-α mRNA expression in cultured Kupffer cells prepared from WT mice. PGI2-IP signaling plays a crucial role in the development and progression of steatohepatitis by modulating the inflammatory response, leading to augmented oxidative stress. We suggest that the PGI2-IP system is an attractive therapeutic target for treating patients with NASH.-Kumei, S., Yuhki, K.-I., Kojima, F., Kashiwagi, H., Imamichi, Y., Okumura, T., Narumiya, S., Ushikubi, F. Prostaglandin I2 suppresses the development of diet-induced nonalcoholic steatohepatitis in mice.
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Affiliation(s)
- Shima Kumei
- Department of Pharmacology, Asahikawa Medical University, Asahikawa, Japan.,Department of General Medicine, Asahikawa Medical University, Asahikawa, Japan
| | - Koh-Ichi Yuhki
- Department of Pharmacology, Asahikawa Medical University, Asahikawa, Japan
| | - Fumiaki Kojima
- Department of Pharmacology, Asahikawa Medical University, Asahikawa, Japan
| | - Hitoshi Kashiwagi
- Department of Pharmacology, Asahikawa Medical University, Asahikawa, Japan
| | - Yoshitaka Imamichi
- Department of Pharmacology, Asahikawa Medical University, Asahikawa, Japan
| | - Toshikatsu Okumura
- Department of General Medicine, Asahikawa Medical University, Asahikawa, Japan
| | - Shuh Narumiya
- Department of Pharmacology, Kyoto University Faculty of Medicine, Kyoto, Japan
| | - Fumitaka Ushikubi
- Department of Pharmacology, Asahikawa Medical University, Asahikawa, Japan
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48
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XIE X, GUO A, WU T, HU Q, HUANG L, YAO C, ZHAO B, ZHANG W, CHI B, LU P, ZHAO Z, FU Z. Preventive Effect of L-Carnitine on the Disorder of Lipid Metabolism and Circadian Clock of Mice Subjected to Chronic Jet-Lag. Physiol Res 2017; 66:801-810. [DOI: 10.33549/physiolres.933543] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Circadian clock plays an essential role in orchestrating daily physiology, and its disruption can evoke metabolic diseases such as obesity. L-Carnitine can reduce blood lipid levels, and ameliorate fatty liver through regulating lipid metabolism. However, whether L-Carnitine administration may affect the disturbance of lipid metabolism and circadian rhythm of mice induced by prolonged circadian disruption is still unknown. Herein, we investigated the effects of L-Carnitine on conditions of circadian clock and lipid metabolism through a chronic jet-lag mice model which was developed by reversing 12 h light/12 h dark cycle every 4 days for a continuous 12 weeks. Results showed that L-Carnitine administration significantly decreased levels of serum glutamic-oxaloacetic transaminase (GOT) and triglycerides (TG), which were remarkably elevated by chronic jet-lag. More importantly, quantitative real-time polymerase chain reaction (qRT-PCR) analysis indicated that L-Carnitine supplementation would effectively counteract the negative alterations in gene expression which related to lipid metabolism (Srebp1, Acaca, Fasn, and Scd1), metabolic regulator (mTOR) and circadian rhythm (Bmal1, Per1, Cry1 and Dec1) in the liver of mice subjected to the chronic jet-lag. As a conclusion, L-Carnitine was partly effective in preventing the disruption of circadian clock and lipid metabolic disorders induced by the chronic jet-lag.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | | | | | - Z. FU
- College of Biotechnology and Bioengineering, Zhejiang University of Technology, Hangzhou, China
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Bellanti F, Villani R, Facciorusso A, Vendemiale G, Serviddio G. Lipid oxidation products in the pathogenesis of non-alcoholic steatohepatitis. Free Radic Biol Med 2017; 111:173-185. [PMID: 28109892 DOI: 10.1016/j.freeradbiomed.2017.01.023] [Citation(s) in RCA: 98] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/27/2016] [Revised: 01/11/2017] [Accepted: 01/15/2017] [Indexed: 02/08/2023]
Abstract
Non-alcoholic fatty liver disease (NAFLD) is the major public health challenge for hepatologists in the twenty-first century. NAFLD comprises a histological spectrum ranging from simple steatosis or fatty liver, to steatohepatitis, fibrosis, and cirrhosis. It can be categorized into two principal phenotypes: (1) non-alcoholic fatty liver (NAFL), and (2) non-alcoholic steatohepatitis (NASH). The mechanisms of NAFLD progression consist of lipid homeostasis alterations, redox unbalance, insulin resistance, and inflammation in the liver. Even though several studies show an association between the levels of lipid oxidation products and disease state, experimental evidence suggests that compounds such as reactive aldehydes and cholesterol oxidation products, in addition to representing hallmarks of hepatic oxidative damage, may behave as active players in liver dysfunction and the development of NAFLD. This review summarizes the processes that contribute to the metabolic alterations occurring in fatty liver that produce fatty acid and cholesterol oxidation products in NAFLD, with a focus on inflammation, the control of insulin signalling, and the transcription factors involved in lipid metabolism.
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Affiliation(s)
- Francesco Bellanti
- C.U.R.E. Centre for Liver Diseases Research and Treatment, Institute of Internal Medicine, Department of Medical and Surgical Sciences, University of Foggia, Foggia 71122, Italy
| | - Rosanna Villani
- C.U.R.E. Centre for Liver Diseases Research and Treatment, Institute of Internal Medicine, Department of Medical and Surgical Sciences, University of Foggia, Foggia 71122, Italy
| | - Antonio Facciorusso
- C.U.R.E. Centre for Liver Diseases Research and Treatment, Institute of Internal Medicine, Department of Medical and Surgical Sciences, University of Foggia, Foggia 71122, Italy
| | - Gianluigi Vendemiale
- C.U.R.E. Centre for Liver Diseases Research and Treatment, Institute of Internal Medicine, Department of Medical and Surgical Sciences, University of Foggia, Foggia 71122, Italy
| | - Gaetano Serviddio
- C.U.R.E. Centre for Liver Diseases Research and Treatment, Institute of Internal Medicine, Department of Medical and Surgical Sciences, University of Foggia, Foggia 71122, Italy.
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Moriishi K. The potential of signal peptide peptidase as a therapeutic target for hepatitis C. Expert Opin Ther Targets 2017; 21:827-836. [PMID: 28820612 DOI: 10.1080/14728222.2017.1369959] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Affiliation(s)
- Kohji Moriishi
- Department of Microbiology, Graduate School of Medical Science, University of Yamanashi, Yamanashi, Japan
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