1
|
Ou S, Tang X, Li Z, Ouyang R, Lei Y, Chen G, Du L. miR-372-3p represses hepatic stellate cell activation via the RhoC/ROCK pathway. Cytotechnology 2025; 77:60. [PMID: 39959789 PMCID: PMC11828770 DOI: 10.1007/s10616-025-00715-9] [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: 09/23/2024] [Accepted: 01/14/2025] [Indexed: 02/18/2025] Open
Abstract
The study was undertaken to determine the mechanism of miR-372-3p activating hepatic stellate cell (HSC). Transforming growth factor-β1 (TGF-β1) induced LX-2 cells were transfected with miR-372-3p mimics and/or RhoC overexpression vector (oe-RhoC), after which the miR-372-3 and RhoC expressions were detected and the biological functions of transfected cells were assessed. The relation between miR-372-3p and RhoC predicted online was validated using the dual-luciferase assay. Protein level of Collagen I (COL I), α-smooth muscle actin (α-SMA), and key proteins in the RhoC/ROCK pathway were determined using western blot. Activated LX-2 cells had decreased miR-372-3p and increased RhoC expression. Overexpression of miR-372-3p led to inhibited LX-2 cell proliferation, accelerated apoptosis, and decreased protein level of COL I and α-SMA, while such an expression pattern can be partially reversed by RhoC overexpression. miR-372-3p can bind and target RhoC expression. miR-372-3p inhibited RhoC expression to block the activation of the Rho/ROCK pathway and thus mediate LX-2 cell proliferation and apoptosis. miR-372-3p mediated RhoC/ROCK pathway to inhibit HSC activation.
Collapse
Affiliation(s)
- Shiyu Ou
- Department of Gastroenterology, Liuzhou Workers’ Hospital (The Fourth Affiliated Hospital of Guangxi Medical University), No. 156 Heping Road, Liuzhou, 545007 Guangxi China
| | - Xiaoling Tang
- Department of Pharmacy, Guangxi Zhuang Autonomous Region Brain Hospital, Liuzhou, 545007 Guangxi China
| | - Zhongzhuan Li
- Department of Gastroenterology, Liuzhou Workers’ Hospital (The Fourth Affiliated Hospital of Guangxi Medical University), No. 156 Heping Road, Liuzhou, 545007 Guangxi China
| | - Rong Ouyang
- Department of Gastroenterology, Liuzhou Workers’ Hospital (The Fourth Affiliated Hospital of Guangxi Medical University), No. 156 Heping Road, Liuzhou, 545007 Guangxi China
| | - Yuan Lei
- Department of Gastroenterology, Liuzhou Workers’ Hospital (The Fourth Affiliated Hospital of Guangxi Medical University), No. 156 Heping Road, Liuzhou, 545007 Guangxi China
| | - Gang Chen
- Department of Gastroenterology, Liuzhou Workers’ Hospital (The Fourth Affiliated Hospital of Guangxi Medical University), No. 156 Heping Road, Liuzhou, 545007 Guangxi China
| | - Ling Du
- Department of Gastroenterology, Liuzhou Workers’ Hospital (The Fourth Affiliated Hospital of Guangxi Medical University), No. 156 Heping Road, Liuzhou, 545007 Guangxi China
| |
Collapse
|
2
|
Huschet LA, Kliem FP, Wienand P, Wunderlich CM, Ribeiro A, Bustos-Martínez I, Barco Á, Wunderlich FT, Lech M, Robles MS. FrozONE: quick cell nucleus enrichment for comprehensive proteomics analysis of frozen tissues. Life Sci Alliance 2025; 8:e202403130. [PMID: 39667914 PMCID: PMC11638322 DOI: 10.26508/lsa.202403130] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2024] [Revised: 12/02/2024] [Accepted: 12/03/2024] [Indexed: 12/14/2024] Open
Abstract
Subcellular fractionation allows for the investigation of compartmentalized processes in individual cellular organelles. Nuclear enrichment methods commonly employ the use of density gradients combined with ultracentrifugation for freshly isolated tissues. Although it is broadly used in combination with proteomics, this approach poses several challenges when it comes to scalability and applicability for frozen material. To overcome these limitations, we developed FrozONE (Frozen Organ Nucleus Enrichment), a nucleus enrichment and proteomics workflow for frozen tissues. By extensively benchmarking our workflow against alternative methods, we showed that FrozONE is a faster, simpler, and more scalable alternative to conventional ultracentrifugation methods. FrozONE allowed for the study, profiling, and classification of nuclear proteomes in different tissues with complex cellular heterogeneity, ensuring optimal nucleus enrichment from different cell types and quantitative resolution for low abundant proteins. In addition to its performance in healthy mouse tissues, FrozONE proved to be very efficient for the characterization of liver nuclear proteome alterations in a pathological condition, diet-induced nonalcoholic steatohepatitis.
Collapse
Affiliation(s)
- Lukas A Huschet
- Institute of Medical Psychology and Biomedical Center (BMC), Faculty of Medicine, LMU, Munich, Germany
| | - Fabian P Kliem
- Institute of Medical Psychology and Biomedical Center (BMC), Faculty of Medicine, LMU, Munich, Germany
| | - Peter Wienand
- Max Planck Institute for Metabolism Research, Center for Molecular Medicine Cologne (CMMC) and Policlinic for Endocrinology, Diabetes, and Preventive Medicine (PEDP), University Hospital Cologne, Cologne, Germany
| | - Claudia M Wunderlich
- Max Planck Institute for Metabolism Research, Center for Molecular Medicine Cologne (CMMC) and Policlinic for Endocrinology, Diabetes, and Preventive Medicine (PEDP), University Hospital Cologne, Cologne, Germany
| | - Andrea Ribeiro
- LMU Klinikum, Medizinische Klinik und Poliklinik IV, Ludwig-Maximilians-Universität München, Munich, Germany
| | - Isabel Bustos-Martínez
- Instituto de Neurociencias (Universidad Miguel Hernández-Consejo Superior de Investigaciones Científicas), Alicante, Spain
| | - Ángel Barco
- Instituto de Neurociencias (Universidad Miguel Hernández-Consejo Superior de Investigaciones Científicas), Alicante, Spain
| | - F Thomas Wunderlich
- Max Planck Institute for Metabolism Research, Center for Molecular Medicine Cologne (CMMC) and Policlinic for Endocrinology, Diabetes, and Preventive Medicine (PEDP), University Hospital Cologne, Cologne, Germany
| | - Maciej Lech
- LMU Klinikum, Medizinische Klinik und Poliklinik IV, Ludwig-Maximilians-Universität München, Munich, Germany
| | - Maria S Robles
- Institute of Medical Psychology and Biomedical Center (BMC), Faculty of Medicine, LMU, Munich, Germany
| |
Collapse
|
3
|
Hong J, Kim YH. Cutting-edge biotherapeutics and advanced delivery strategies for the treatment of metabolic dysfunction-associated steatotic liver disease spectrum. J Control Release 2025; 380:433-456. [PMID: 39923856 DOI: 10.1016/j.jconrel.2025.02.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2024] [Revised: 12/22/2024] [Accepted: 02/04/2025] [Indexed: 02/11/2025]
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD), a condition with the potential to progress into liver cirrhosis or hepatocellular carcinoma, has become a significant global health concern due to its increasing prevalence alongside obesity and metabolic syndrome. Despite the promise of existing therapies such as thyroid hormone receptor-β (THR-β) agonists, PPAR agonists, FXR agonists, and GLP-1 receptor agonists, their effectiveness is limited by the complexity of the metabolic, inflammatory, and fibrotic pathways that drive MASLD progression, encompassing steatosis, metabolic dysfunction-associated steatohepatitis (MASH), and reversible liver fibrosis. Recent advances in targeted therapeutics, including RNA interference (RNAi), mRNA-based gene therapies, monoclonal antibodies, proteolysis-targeting chimeras (PROTAC), peptide-based strategies, cell-based therapies such as CAR-modified immune cells and stem cells, and extracellular vesicle-based approaches, have emerged as promising interventions. Alongside these developments, innovative drug delivery systems are being actively researched to enhance the stability, precision, and therapeutic efficacy of these biotherapeutics. These delivery strategies aim to optimize biodistribution, improve target-specific action, and reduce systemic exposure, thus addressing critical limitations of existing treatment modalities. This review provides a comprehensive exploration of the underlying biological mechanisms of MASLD and evaluates the potential of these cutting-edge biotherapeutics in synergy with advanced delivery approaches to address unmet clinical needs. By integrating fundamental disease biology with translational advancements, it aims to highlight future directions for the development of effective, targeted treatments for MASLD and its associated complications.
Collapse
Affiliation(s)
- Juhyeong Hong
- Department of Bioengineering, Institute for Bioengineering and Biopharmaceutical Research Hanyang University, 04763 Seoul, South Korea; Education and Research Group for Biopharmaceutical Innovation Leader, Hanyang University, 04763 Seoul, South Korea
| | - Yong-Hee Kim
- Department of Bioengineering, Institute for Bioengineering and Biopharmaceutical Research Hanyang University, 04763 Seoul, South Korea; Education and Research Group for Biopharmaceutical Innovation Leader, Hanyang University, 04763 Seoul, South Korea; Cursus Bio Inc., Icure Tower, Gangnam-gu, Seoul 06170, Republic of Korea.
| |
Collapse
|
4
|
Ma X, Huang T, Chen X, Li Q, Liao M, Fu L, Huang J, Yuan K, Wang Z, Zeng Y. Molecular mechanisms in liver repair and regeneration: from physiology to therapeutics. Signal Transduct Target Ther 2025; 10:63. [PMID: 39920130 PMCID: PMC11806117 DOI: 10.1038/s41392-024-02104-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2023] [Revised: 09/02/2024] [Accepted: 12/12/2024] [Indexed: 02/09/2025] Open
Abstract
Liver repair and regeneration are crucial physiological responses to hepatic injury and are orchestrated through intricate cellular and molecular networks. This review systematically delineates advancements in the field, emphasizing the essential roles played by diverse liver cell types. Their coordinated actions, supported by complex crosstalk within the liver microenvironment, are pivotal to enhancing regenerative outcomes. Recent molecular investigations have elucidated key signaling pathways involved in liver injury and regeneration. Viewed through the lens of metabolic reprogramming, these pathways highlight how shifts in glucose, lipid, and amino acid metabolism support the cellular functions essential for liver repair and regeneration. An analysis of regenerative variability across pathological states reveals how disease conditions influence these dynamics, guiding the development of novel therapeutic strategies and advanced techniques to enhance liver repair and regeneration. Bridging laboratory findings with practical applications, recent clinical trials highlight the potential of optimizing liver regeneration strategies. These trials offer valuable insights into the effectiveness of novel therapies and underscore significant progress in translational research. In conclusion, this review intricately links molecular insights to therapeutic frontiers, systematically charting the trajectory from fundamental physiological mechanisms to innovative clinical applications in liver repair and regeneration.
Collapse
Affiliation(s)
- Xiao Ma
- Division of Liver Surgery, Department of General Surgery and Laboratory of Liver Surgery, and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Tengda Huang
- Division of Liver Surgery, Department of General Surgery and Laboratory of Liver Surgery, and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Xiangzheng Chen
- Division of Liver Surgery, Department of General Surgery and Laboratory of Liver Surgery, and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Qian Li
- Division of Liver Surgery, Department of General Surgery and Laboratory of Liver Surgery, and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Mingheng Liao
- Division of Liver Surgery, Department of General Surgery and Laboratory of Liver Surgery, and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Li Fu
- Division of Liver Surgery, Department of General Surgery and Laboratory of Liver Surgery, and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Jiwei Huang
- Division of Liver Surgery, Department of General Surgery and Laboratory of Liver Surgery, and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Kefei Yuan
- Division of Liver Surgery, Department of General Surgery and Laboratory of Liver Surgery, and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Zhen Wang
- Division of Liver Surgery, Department of General Surgery and Laboratory of Liver Surgery, and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China.
| | - Yong Zeng
- Division of Liver Surgery, Department of General Surgery and Laboratory of Liver Surgery, and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China.
| |
Collapse
|
5
|
Sun Y, Yuan X, Hu Z, Li Y. Harnessing nuclear receptors to modulate hepatic stellate cell activation for liver fibrosis resolution. Biochem Pharmacol 2025; 232:116730. [PMID: 39710274 DOI: 10.1016/j.bcp.2024.116730] [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: 06/10/2024] [Revised: 12/04/2024] [Accepted: 12/19/2024] [Indexed: 12/24/2024]
Abstract
With the recent approval of Resmetirom as the first drug targeting nuclear receptors for metabolic dysfunction-associated steatohepatitis (MASH), there is promising way to treat MASH-associated liver fibrosis. However, liver fibrosis can arise from various pathogenic factors, and effective treatments for fibrosis due to other causes remain elusive. The activation of hepatic stellate cells (HSCs) represents a central link in the pathogenesis of hepatic fibrosis. Therefore, harnessing nuclear receptors to modulate HSC activation may be an effective approach to resolving the complex liver fibrosis caused by various factors. In this comprehensive review, we systematically explore the structure and physiological functions of nuclear receptors, shedding light on their multifaceted roles in HSC activation. Recent advancements in drug development targeting nuclear receptors are discussed, providing insights into their potential as rational and effective therapeutic targets for modulating HSC activation in the context of liver fibrosis. By elucidating the intricate interplay between nuclear receptors and HSC activation, this review contributes to the discovery of new nuclear receptor targets in HSCs for resolving hepatic fibrosis.
Collapse
Affiliation(s)
- Yaxin Sun
- Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China; Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan, China; University of Chinese Academy of Sciences, Beijing, China
| | - Xiaoyan Yuan
- Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China; Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan, China; University of Chinese Academy of Sciences, Beijing, China
| | - Zhenhua Hu
- Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan, China; Department of Health and Nursing, Nanfang College of Sun Yat-sen University, Guangzhou, China.
| | - Yuanyuan Li
- Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China; Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan, China; University of Chinese Academy of Sciences, Beijing, China.
| |
Collapse
|
6
|
Xie J, Chen S, Chen Y, Tong J, Huang H, Liao J, Sun J, Cong L, Zeng Y. FFA intervention on LO2 cells mediates SNX-10 synthesis and regulates MMP9 secretion in LX2 cells via TGF-β1. Arch Biochem Biophys 2025; 764:110255. [PMID: 39662717 DOI: 10.1016/j.abb.2024.110255] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2024] [Revised: 11/10/2024] [Accepted: 11/29/2024] [Indexed: 12/13/2024]
Abstract
BACKGROUND Metabolic-associated fatty liver disease (MAFLD) is a public health concern. Transforming growth factor-β1(TGF-β1) plays an important regulatory role in multiple MAFLD stages, as it can promote the expression of matrix metalloproteinase-9 (MMP9) and promote liver fibrosis. Sorting nexin protein-10 (SNX-10) may be involved in the occurrence and development of fatty liver disease. METHODS Free fatty acids (FFA) treatment was used to simulate the cellular lipid deposition stage of MAFLD and the interactions between cells were simulated via LX2 and LO2 coculture. The molecular interaction between the two cell types was studied via ELISA, immunoprecipitation, qPCR, and western blotting. RESULTS In FFA-treated LO2 cells, intracellular TGF-β1 expression increased as lipid deposition increased. FFA-treated LO2 cells promoted the expression and secretion of MMP9 by LX2 cells through paracrine pathways. MMP9 secretion decreased with decreasing SNX-10 expression in LX2 cells. The interaction between MMP9 and SNX-10 was confirmed by coimmunoprecipitation. TGF-β1 promoted the synthesis of SNX-10 through the p38 MAPK pathway, and SNX-10 affected the secretion of MMP9 through protein interactions, thereby affecting the development of liver fibrosis. CONCLUSIONS FFA induced lipid deposition in LO2 cells, and TGF-β1 mediated the p38 MAPK pathway to promote SNX-10 synthesis and stimulate MMP9 secretion, thereby regulating the involvement of LX2 in the process of liver fibrosis.
Collapse
Affiliation(s)
- Jianhui Xie
- Department of Endocrinology and Metabolic Diseases, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, Guangdong, China
| | - Shiyan Chen
- Department of Endocrinology and Metabolic Diseases, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, Guangdong, China
| | - Yangli Chen
- Department of Endocrinology and Metabolic Diseases, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, Guangdong, China
| | - Junlu Tong
- Department of Endocrinology and Metabolic Diseases, The First Affiliated Hospital of Wannan Medical College, Yijishan Hospital, Wuhu, Anhui, China
| | - Huijie Huang
- Department of Endocrinology and Metabolic Diseases, The First Huizhou Affiliated Hospital of Guangdong Medical University, Huizhou, Guangdong, China
| | - Jingwen Liao
- Department of Endocrinology and Metabolic Diseases, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, Guangdong, China
| | - Jixin Sun
- Department of Endocrinology and Metabolic Diseases, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, Guangdong, China
| | - Li Cong
- Department of Endocrinology and Metabolic Diseases, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, Guangdong, China.
| | - Yingjuan Zeng
- Department of Endocrinology and Metabolic Diseases, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, Guangdong, China.
| |
Collapse
|
7
|
Wang G, Yin Y, Lv R, Ling X, Cao H, Liu H, Wu J, Gao Y, Zhang K, Wang Y. Taraxasterol extracted from Ixeridium gramineum (Fisch.) Tzvel. Attenuated D-GalN/LPS-induced fulminant hepatitis by modulating the JAK/STAT and TNF signalling pathways. JOURNAL OF ETHNOPHARMACOLOGY 2025; 340:119256. [PMID: 39701218 DOI: 10.1016/j.jep.2024.119256] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/15/2024] [Revised: 12/09/2024] [Accepted: 12/15/2024] [Indexed: 12/21/2024]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Taraxasterol (TAR), a compound highly abundant and easily obtainable from Tibetan medicine Ixeridium gramineum (Fisch.) Tzvel., exhibits a variety of biological effects, including hepatoprotective, anti-inflammatory, and antioxidant activities. AIM OF THE STUDY To investigated the protective role and underlying mechanisms of TAR in fulminant hepatitis (FH) through the regulation of oxidative stress, inflammatory responses, and apoptosis by modulating the JAK/STAT and TNF signalling pathways. MATERIAL AND METHODS The study used Kunming mice to establish a D-GalN/LPS-induced FH model, which was divided into the following groups: Control group, D-GalN/LPS group, D-GalN/LPS + Silymarin group, D-GalN/LPS + TAR 2.5 group, D-GalN/LPS + TAR 5 group, D-GalN/LPS + TAR 10 group, and TAR 10 group. H&E staining and biochemical analyses were employed to evaluate liver pathological changes. Oxidative stress factors and inflammatory response were assessed via ELISA. RNA sequencing analysis was used to detect changes in inflammatory factor genes and apoptosis genes with TAR intervention in liver tissues. The distribution of the proteins p-STAT3 and p-JNK in liver tissues was ascertained using immunohistochemical staining. In vitro experiments were conducted on RAW264.7 cells exposed to LPS and TAR. Apoptosis was evaluated via flow cytometry and Hoechst 33258 staining. Immunofluorescence staining was employed to determine the protein expression levels of p-STAT3 and p-JNK in RAW264.7 cells. Gene and protein expression in the JAK/STAT and TNF signalling pathways, as well as apoptosis, were analyzed using qRT-PCR and Western blotting. RESULTS TAR effectively reduced hepatocyte necrosis, diminished inflammatory factor release, inhibited oxidative stress, significantly decreased the apoptosis of RAW264.7 cells, inhibited the protein expressions of p-JAK2, p-STAT3, p-MEK4, p-JNK, Caspase-3, Caspase-8, and Bax, and increased the protein expressions of SOCS3 and Bcl-2. CONCLUSION TAR prevents D-GalN/LPS-induced FH by regulating the JAK/STAT and TNF signalling pathways and apoptosis, demonstrating its therapeutic potential in treating liver diseases.
Collapse
Affiliation(s)
- Gang Wang
- Department of Anesthesiology, Affiliated hospital of Guilin Medical University, China
| | - Yifan Yin
- Pharmacology Laboratory of Prevention and Treatment of High Incidence of Disease, Guilin Medical University, 541004, Guilin, Guangxi, China; Guangxi Key Laboratory of Diabetic Systems Medicine, The Second Affiliated Hospital of Guilin Medical University, 541004, Guilin, Guangxi, China
| | - Rui Lv
- Pharmacology Laboratory of Prevention and Treatment of High Incidence of Disease, Guilin Medical University, 541004, Guilin, Guangxi, China; Guangxi Key Laboratory of Diabetic Systems Medicine, The Second Affiliated Hospital of Guilin Medical University, 541004, Guilin, Guangxi, China
| | - Xiumei Ling
- Department of Anesthesiology, Affiliated hospital of Guilin Medical University, China
| | - Houkang Cao
- Pharmacology Laboratory of Prevention and Treatment of High Incidence of Disease, Guilin Medical University, 541004, Guilin, Guangxi, China; Guangxi Key Laboratory of Diabetic Systems Medicine, The Second Affiliated Hospital of Guilin Medical University, 541004, Guilin, Guangxi, China
| | - Haiping Liu
- Pharmacology Laboratory of Prevention and Treatment of High Incidence of Disease, Guilin Medical University, 541004, Guilin, Guangxi, China
| | - Jianzhao Wu
- Pharmacology Laboratory of Prevention and Treatment of High Incidence of Disease, Guilin Medical University, 541004, Guilin, Guangxi, China
| | - Ya Gao
- Pharmacology Laboratory of Prevention and Treatment of High Incidence of Disease, Guilin Medical University, 541004, Guilin, Guangxi, China; Guangxi Key Laboratory of Diabetic Systems Medicine, The Second Affiliated Hospital of Guilin Medical University, 541004, Guilin, Guangxi, China.
| | - Kefeng Zhang
- Pharmacology Laboratory of Prevention and Treatment of High Incidence of Disease, Guilin Medical University, 541004, Guilin, Guangxi, China; Guangxi Key Laboratory of Diabetic Systems Medicine, The Second Affiliated Hospital of Guilin Medical University, 541004, Guilin, Guangxi, China.
| | - Yongwang Wang
- Department of Anesthesiology, Affiliated hospital of Guilin Medical University, China.
| |
Collapse
|
8
|
Xue W, Liu H, Su Z, Wang S, Cheng J, Pan Y, Zhang L. Qinggan Yipi capsule ameliorates hepatic fibrosis in rats by down-regulating the TGF-β1/Smad2/3 signaling pathway and improving gut microbiota imbalance. Front Pharmacol 2025; 16:1525914. [PMID: 39925848 PMCID: PMC11802500 DOI: 10.3389/fphar.2025.1525914] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2024] [Accepted: 01/02/2025] [Indexed: 02/11/2025] Open
Abstract
Background and objective Qinggan Yipi Capsule (QgYp) is a hospital preparation that has been used for many years in the treatment of chronic liver diseases. However, the mechanism of QgYp in ameliorating hepatic fibrosis (HF) remains unclear. This study aims to clarify the anti-liver fibrosis effect of QgYp and its mechanism of action. Methods This study uses a carbon tetrachloride (CCl4) induced HF rat model and TGF-β1 stimulated HSC-T6 cell line (rat HSCs) as experimental models. The therapeutic effects were evaluated through pathology, biochemical tests, and ELISA. The therapeutic mechanism of QgYp for HF was predicted through network pharmacology. The expression of TGF-β1/Smad2/3 related proteins was detected by qPCR analysis and Western blot analysis. The composition of the gut microbiota was analyzed using 16S rRNA gene sequencing. Results Histopathological analysis, serum biochemical tests, and ELISA measurements showed that QgYp effectively decreased the levels of ALT, AST, HA, LN, PCIII, and IV-C while improving collagen deposition and hepatocyte necrosis. Protein-protein interaction (PPI) network analysis screened HF-related genes, including peroxisome proliferator-activated receptor gamma (PPARG), tumor necrosis factor (TNF), and TGF-β1. GO and KEGG analyses indicated that QgYp significantly affects TGF-β signaling pathway. In addition, the results of qPCR and Western blot analysis from both in vitro and in vivo experiments indicated that QgYp significantly downregulated the expression of proteins and mRNA associated with the TGF-β1/Smad2/3 pathway. The 16S rDNA gene sequencing results showed that QgYp can increase the diversity and richness of the gut microbiota in HF rats and alter the composition of the gut microbiota. Conclusion QgYp could effectively ameliorate HF, and this effect might be connected to the downregulation of the TGF-β1/Smad2/3 pathway, the suppression of HSCs activation, and regulation of gut microbiota dysbiosis.
Collapse
Affiliation(s)
- Wenjing Xue
- Key Laboratory for Evaluation and Transformation of Wu Men Medical School’s Empirical Prescriptions, Suzhou Traditional Chinese Medicine Hospital, Affiliated to Nanjing University of Chinese Medicine, Suzhou, China
| | - Haiqing Liu
- Key Laboratory for Evaluation and Transformation of Wu Men Medical School’s Empirical Prescriptions, Suzhou Traditional Chinese Medicine Hospital, Affiliated to Nanjing University of Chinese Medicine, Suzhou, China
| | - Ziheng Su
- Department of Pharmacy, Affiliated Hospital of Hebei University, Baoding, China
| | - Siqi Wang
- Department of Pharmacy, Suzhou Fifth People’s Hospital, Suzhou, China
| | - Junping Cheng
- Key Laboratory for Evaluation and Transformation of Wu Men Medical School’s Empirical Prescriptions, Suzhou Traditional Chinese Medicine Hospital, Affiliated to Nanjing University of Chinese Medicine, Suzhou, China
| | - Yunzhi Pan
- Department of Pharmacy, Suzhou Fifth People’s Hospital, Suzhou, China
| | - Lurong Zhang
- Key Laboratory for Evaluation and Transformation of Wu Men Medical School’s Empirical Prescriptions, Suzhou Traditional Chinese Medicine Hospital, Affiliated to Nanjing University of Chinese Medicine, Suzhou, China
| |
Collapse
|
9
|
Fernandez-Canadas I, Badajoz A, Jimenez-Gonzalez J, Wirenfeldt M, Paniagua-Torija B, Bravo-Jimenez C, Del Cerro M, Arevalo-Martin A, Garcia-Ovejero D. Spinal cord injury induces transient activation of hepatic stellate cells in rat liver. Sci Rep 2025; 15:2826. [PMID: 39843526 PMCID: PMC11754611 DOI: 10.1038/s41598-025-87131-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2024] [Accepted: 01/16/2025] [Indexed: 01/24/2025] Open
Abstract
Spinal cord injury (SCI) causes abnormal liver function, the development of metabolic dysfunction-associated steatotic liver disease features and metabolic impairment in patients. Experimental models also demonstrate acute and chronic changes in the liver that may, in turn, affect SCI recovery. These changes have collectively been proposed to contribute to the development of a SCI-induced metabolic dysfunction-associated steatohepatitis (MASH). However, none of the existent studies have focused on hepatic stellate cells (HSCs), liver resident cells that are the primary drivers of collagen deposition and fibrosis following sustained liver damage. Here, we describe the transient activation of HSCs after a thoracic contusion in rats, considered a clinically relevant model of experimental SCI. We studied HSC during the time course of SCI, from 1 to 45 days post injury. We found a transient activation of HSCs after SCI, beginning with the acute downregulation of Glial Fibrillar Acidic Protein 1dpi. This is followed by a morphological and phenotypical transformation into alpha-smooth muscle actin (ACTA2/SMA) immunoreactive myofibroblast-like cells, peaking at 14 days post-injury and returning to control-like levels at later timepoints (45 days post-injury). These changes are not accompanied by fibrosis development but collagen deposition in peri-portal areas is observed at 45 days.
Collapse
Affiliation(s)
- Inmaculada Fernandez-Canadas
- Laboratorio de Neuroinflamacion i2-06, Hospital Nacional de Paraplejicos, Finca La Peraleda s/n, Toledo, 45071, Spain
| | - Alejandro Badajoz
- Laboratorio de Neuroinflamacion i2-06, Hospital Nacional de Paraplejicos, Finca La Peraleda s/n, Toledo, 45071, Spain
| | - Jesús Jimenez-Gonzalez
- Laboratorio de Neuroinflamacion i2-06, Hospital Nacional de Paraplejicos, Finca La Peraleda s/n, Toledo, 45071, Spain
| | - Martin Wirenfeldt
- Department of Pathology, University Hospital of Southern Denmark, Esbjerg, DK-6000, Denmark
- Department of Regional Health Research, BRIDGE (Brain Research-Inter Disciplinary Guided Excellence), University of Southern Denmark, Odense, DK-5230, Denmark
| | - Beatriz Paniagua-Torija
- Laboratorio de Neuroinflamacion i2-06, Hospital Nacional de Paraplejicos, Finca La Peraleda s/n, Toledo, 45071, Spain
| | - Clara Bravo-Jimenez
- Laboratorio de Neuroinflamacion i2-06, Hospital Nacional de Paraplejicos, Finca La Peraleda s/n, Toledo, 45071, Spain
| | - Mar Del Cerro
- Laboratorio de Neuroinflamacion i2-06, Hospital Nacional de Paraplejicos, Finca La Peraleda s/n, Toledo, 45071, Spain
| | - Angel Arevalo-Martin
- Laboratorio de Neuroinflamacion i2-06, Hospital Nacional de Paraplejicos, Finca La Peraleda s/n, Toledo, 45071, Spain.
| | - Daniel Garcia-Ovejero
- Laboratorio de Neuroinflamacion i2-06, Hospital Nacional de Paraplejicos, Finca La Peraleda s/n, Toledo, 45071, Spain.
| |
Collapse
|
10
|
Yan M, Cui Y, Xiang Q. Metabolism of hepatic stellate cells in chronic liver diseases: emerging molecular and therapeutic interventions. Theranostics 2025; 15:1715-1740. [PMID: 39897543 PMCID: PMC11780521 DOI: 10.7150/thno.106597] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2024] [Accepted: 12/10/2024] [Indexed: 02/04/2025] Open
Abstract
Chronic liver diseases, primarily metabolic dysfunction-associated steatotic liver disease (MASLD), metabolic and metabolic dysfunction-associated alcoholic liver disease (MetALD), and viral hepatitis, can lead to liver fibrosis, cirrhosis, and cancer. Hepatic stellate cell (HSC) activation plays a central role in the development of myofibroblasts and fibrogenesis in chronic liver diseases. However, HSC activation is influenced by the complex microenvironments within the liver, which are largely shaped by the interactions between HSCs and various other cell types. Changes in HSC phenotypes and metabolic mechanisms involve glucose, lipid, and cholesterol metabolism, oxidative stress, activation of the unfolded protein response (UPR), autophagy, ferroptosis, senescence, and nuclear receptors. Clinical interventions targeting these pathways have shown promising results in addressing liver inflammation and fibrosis, as well as in modulating glucose and lipid metabolism and metabolic stress responses. Therefore, a comprehensive understanding of HSC phenotypes and metabolic mechanisms presents opportunities for novel therapeutic approaches aimed at halting or even reversing chronic liver diseases.
Collapse
Affiliation(s)
- Mengyao Yan
- Institute of Clinical Pharmacology, Peking University First Hospital, Beijing, China
| | - Yimin Cui
- Institute of Clinical Pharmacology, Peking University First Hospital, Beijing, China
- Department of Pharmacy Administration and Clinical Pharmacy, School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing, China
| | - Qian Xiang
- Institute of Clinical Pharmacology, Peking University First Hospital, Beijing, China
- Department of Pharmacy Administration and Clinical Pharmacy, School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing, China
| |
Collapse
|
11
|
Hao LS, Ji JX, Jiang MY, Song J, Chen PP, Zhan ZY, Miao XJ, Gao YY, Wang W, Liu T. Effects of changes in SHP2 expression on liver fibrosis by influencing the apoptosis of hepatic stellate cells. APMIS 2025; 133:e13487. [PMID: 39500724 DOI: 10.1111/apm.13487] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2024] [Accepted: 10/21/2024] [Indexed: 12/18/2024]
Abstract
Accumulating research has revealed that src-homology domain 2-containing protein tyrosine phosphatase-2 (SHP2), an oncogenic protein tyrosine phosphatase, is associated with liver fibrosis. Currently, it is still unclear whether SHP2 affects liver fibrosis by influencing the apoptosis of hepatic stellate cells (HSC). In present study, we investigate effects of SHP2 expression changes on liver fibrosis, with special emphasis on the apoptosis of HSC. Using adenovirus vector, wild-type SHP2 gene and short hairpin RNA targeting SHP2 were introduced into rats with liver fibrosis and LX-2 cells in vitro. The expressions of type I and III collagen, pathological and functional changes, collagen deposition in rat liver and apoptosis of LX-2 cells were detected by immunohistochemical and HE staining, automated biochemical analyzer, Masson trichrome staining, and TUNEL. This study showed that overexpression of SHP2 exacerbated dysfunction, inflammatory damage, collagen deposition and increased expression of type I and III collagen in rat liver reduced apoptosis of LX-2 cells. On the contrary, low expression of SHP2 alleviated the aforementioned detection indicators of rats and promoted apoptosis of LX-2 cells. In conclusion, the downregulation of SHP2 expression alleviates liver fibrosis by inducing the apoptosis of HSC, while overexpressed SHP2 exacerbates liver fibrosis by inhibiting the apoptosis of HSC.
Collapse
Affiliation(s)
- Li-Sen Hao
- Department of Gastroenterology, Affiliated Hospital of North China University of Science and Technology, Tangshan, Hebei Province, China
| | - Jing-Xiu Ji
- Department of Gastroenterology, Affiliated Hospital of North China University of Science and Technology, Tangshan, Hebei Province, China
| | - Mei-Yu Jiang
- Department of Gastroenterology, Affiliated Hospital of North China University of Science and Technology, Tangshan, Hebei Province, China
| | - Jie Song
- Department of Gastroenterology, Affiliated Hospital of North China University of Science and Technology, Tangshan, Hebei Province, China
| | - Pan-Pan Chen
- Department of Gastroenterology, Affiliated Hospital of North China University of Science and Technology, Tangshan, Hebei Province, China
| | - Zong-Yuan Zhan
- Department of Gastroenterology, Affiliated Hospital of North China University of Science and Technology, Tangshan, Hebei Province, China
| | - Xiao-Jia Miao
- Department of Gastroenterology, Affiliated Hospital of North China University of Science and Technology, Tangshan, Hebei Province, China
| | - Ying-Ying Gao
- Department of Gastroenterology, Affiliated Hospital of North China University of Science and Technology, Tangshan, Hebei Province, China
| | - Wei Wang
- Department of Gastroenterology, Affiliated Hospital of North China University of Science and Technology, Tangshan, Hebei Province, China
| | - Tian Liu
- Department of Gastroenterology, Affiliated Hospital of North China University of Science and Technology, Tangshan, Hebei Province, China
| |
Collapse
|
12
|
Colca JR, McCommis KS. Metabolic dysfunction and insulin sensitizers in acute and chronic disease. Expert Opin Investig Drugs 2025; 34:17-26. [PMID: 39912680 DOI: 10.1080/13543784.2025.2463086] [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: 09/09/2024] [Revised: 01/09/2025] [Accepted: 02/02/2025] [Indexed: 02/07/2025]
Abstract
INTRODUCTION The concept of insulin resistance has been a major topic for more than 5 decades. While there are several treatments that may impact insulin resistance, this pathology is uniquely addressed by mitochondrially directed thiazolidinedione (TZD) insulin sensitizers. Understanding of this mechanism of action and consideration of 'insulin resistance' as a consequence of metabolic inflammation allows a new paradigm for approaching chronic diseases. AREAS COVERED We review evolving understanding of the mitochondrial pyruvate carrier (MPC) as a mitochondrial mechanism of action of the TZD insulin sensitizers and discuss how reprogramming of mitochondrial metabolism impacts pleotropic pharmacology in multiple tissues. Additional lines of investigation are proposed. EXPERT OPINION A change in paradigm can facilitate rethinking of insulin sensitizers in clinical trials, specifically beyond the treatment of frank type 2 diabetes. There should be broader clinical evaluation of insulin sensitizers in combination with weight loss and lifestyle approaches across diseases/syndromes associated with insulin resistance. Finally, 'connecting all the dots' to unwind the interconnectedness of cell biology involved in the syndromes impacted by metabolic dysfunction and the efficacy of TZD insulin sensitizers may also uncover new molecular targets. New studies should facilitate the discovery and development of novel pharmacologic agents.
Collapse
Affiliation(s)
- Jerry R Colca
- Research and Development, Cirius Therapeutics, Kalamazoo, MI, USA
| | - Kyle S McCommis
- Biochemistry and Molecular Biology, St. Louis University, St. Louis, MO, USA
| |
Collapse
|
13
|
Liu Y, Yin W. CD36 in liver diseases. Hepatol Commun 2025; 9:e0623. [PMID: 39774047 PMCID: PMC11717518 DOI: 10.1097/hc9.0000000000000623] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/15/2024] [Accepted: 11/25/2024] [Indexed: 01/11/2025] Open
Abstract
Cluster of differentiation 36 (CD36) is a transmembrane glycoprotein with the ability to bind to multiple ligands and perform diverse functions. Through the recognition of long-chain fatty acids, proteins containing thrombospondin structural homology repeat domains such as thrombospondin-1, and molecules with molecular structures consistent with danger- or pathogen-associated molecular patterns, CD36 participates in various physiological and pathological processes of the body. CD36 is widely expressed in various cell types, including hepatocytes and KCs in the liver, where it plays a pivotal role in lipid metabolism, inflammation, and oxidative stress. Accumulating evidence suggests that CD36 plays a complex role in the development of nonalcoholic simple fatty liver disease and NASH and contributes to the pathogenesis of inflammatory liver injury, hepatitis B/hepatitis C, liver fibrosis, and liver cancer. This review summarizes the current understanding of the structural properties, expression patterns, and functional mechanisms of CD36 in the context of liver pathophysiology. Furthermore, the potential of CD36 as a therapeutic target for the prevention and treatment of liver diseases is highlighted.
Collapse
|
14
|
Hamamah S, Iatcu OC, Covasa M. Dietary Influences on Gut Microbiota and Their Role in Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD). Nutrients 2024; 17:143. [PMID: 39796579 PMCID: PMC11722922 DOI: 10.3390/nu17010143] [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: 12/15/2024] [Revised: 12/27/2024] [Accepted: 12/30/2024] [Indexed: 01/13/2025] Open
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD) is a major contributor to liver-related morbidity, cardiovascular disease, and metabolic complications. Lifestyle interventions, including diet and exercise, are first line in treating MASLD. Dietary approaches such as the low-glycemic-index Mediterranean diet, the ketogenic diet, intermittent fasting, and high fiber diets have demonstrated potential in addressing the metabolic dysfunction underlying this condition. The development and progression of MASLD are closely associated with taxonomic shifts in gut microbial communities, a relationship well-documented in the literature. Given the importance of diet as a primary treatment for MASLD, it is important to understand how gut microbiota and their metabolic byproducts mediate favorable outcomes induced by healthy dietary patterns. Conversely, microbiota changes conferred by unhealthy dietary patterns such as the Western diet may induce dysbiosis and influence steatotic liver disease through promoting hepatic inflammation, up-regulating lipogenesis, dysregulating bile acid metabolism, increasing insulin resistance, and causing oxidative damage in hepatocytes. Although emerging evidence has identified links between diet, microbiota, and development of MASLD, significant gaps remain in understanding specific microbial roles, metabolite pathways, host interactions, and causal relationships. Therefore, this review aims to provide mechanistic insights into the role of microbiota-mediated processes through the analysis of both healthy and unhealthy dietary patterns and their contribution to MASLD pathophysiology. By better elucidating the interplay between dietary nutrients, microbiota-mediated processes, and the onset and progression of steatotic liver disease, this work aims to identify new opportunities for targeted dietary interventions to treat MASLD efficiently.
Collapse
Affiliation(s)
- Sevag Hamamah
- Department of Internal Medicine, Scripps Mercy Hospital, San Diego, CA 92103, USA;
| | - Oana C. Iatcu
- Department of Biomedical Sciences, College of Medicine and Biological Science, University of Suceava, 720229 Suceava, Romania;
| | - Mihai Covasa
- Department of Biomedical Sciences, College of Medicine and Biological Science, University of Suceava, 720229 Suceava, Romania;
| |
Collapse
|
15
|
Chen T, Yang W, Dong R, Yao H, Sun M, Wang J, Zhou Q, Xu J. The effect and application of adiponectin in hepatic fibrosis. Gastroenterol Rep (Oxf) 2024; 12:goae108. [PMID: 39737222 PMCID: PMC11683834 DOI: 10.1093/gastro/goae108] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/16/2024] [Revised: 07/04/2024] [Accepted: 09/24/2024] [Indexed: 01/01/2025] Open
Abstract
Hepatic fibrosis, a degenerative liver lesion, significantly contributes to the deterioration and mortality among patients with chronic liver diseases. The condition arises from various factors including toxins, such as alcohol, infections like different types of viral hepatitis, and metabolic diseases. Currently, there are no effective treatments available for liver fibrosis. Recent research has shown that adiponectin (ADPN) exhibits inhibitory effects on hepatic fibrosis. ADPN, an adipocytokine secreted by mature adipocytes, features receptors that are widely distributed across multiple tissues, especially the liver. In the liver, direct effects of ADPN on liver fibrosis include reducing inflammation and regulating hepatic stellate cell proliferation and migration. And its indirect effects include alleviating hepatic endoplasmic reticulum stress and reducing inflammation in hepatic lobules, thereby mitigating hepatic fibrosis. This review aims to elucidate the regulatory role of ADPN in liver fibrosis, explore how ADPN and its receptors alleviate endoplasmic reticulum stress, summarize ADPN detection methods, and discuss its potential as a novel marker and therapeutic agent in combating hepatic fibrosis.
Collapse
Affiliation(s)
- Taoran Chen
- Department of Laboratory Medicine, First Hospital of Jilin University, Changchun, Jilin, P. R. China
| | - Wenjing Yang
- Department of Laboratory Medicine, First Hospital of Jilin University, Changchun, Jilin, P. R. China
| | - Rongrong Dong
- Department of Laboratory Medicine, First Hospital of Jilin University, Changchun, Jilin, P. R. China
| | - Han Yao
- Department of Laboratory Medicine, First Hospital of Jilin University, Changchun, Jilin, P. R. China
| | - Miao Sun
- Department of Laboratory Medicine, First Hospital of Jilin University, Changchun, Jilin, P. R. China
| | - Jiaxin Wang
- Department of Laboratory Medicine, First Hospital of Jilin University, Changchun, Jilin, P. R. China
| | - Qi Zhou
- Department of Pediatrics, First Hospital of Jilin University, Changchun, Jilin, P. R. China
| | - Jiancheng Xu
- Department of Laboratory Medicine, First Hospital of Jilin University, Changchun, Jilin, P. R. China
| |
Collapse
|
16
|
Sohn M, Kim S, Jeong HJ, Ko IY, Moon JW, Lee D, Oh J. Strategic Optimization of the Middle Domain IIIA in RBP-Albumin IIIA-IB Fusion Protein to Enhance Productivity and Thermostability. Int J Mol Sci 2024; 26:137. [PMID: 39795995 PMCID: PMC11720212 DOI: 10.3390/ijms26010137] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2024] [Revised: 12/24/2024] [Accepted: 12/25/2024] [Indexed: 01/13/2025] Open
Abstract
The protein therapeutics market, including antibody and fusion proteins, has experienced steady growth over the past decade, underscoring the importance of optimizing amino acid sequences. In our previous study, we developed a fusion protein, R31, which combines retinol-binding protein (RBP) with albumin domains IIIA and IB, linked by a sequence (AAAA), and includes an additional disulfide bond (N227C-V254C) in IIIA. This fusion protein effectively inhibited hepatic stellate cell activation. In this study, we further optimized the sequence. The G176K mutation at the C-terminus of RBP altered the initiation site of the first α-helix in domain IIIA, shifting it from P182 to K176, and promoted polar interactions between K176 and adjacent residues, enhancing the rigidity of the RBP/IIIA interface. The introduction of an additional disulfide bond (V231C/Y250C) connecting helices 3 and 4 in IIIA resulted in a three-fold increase in productivity and a 2 °C improvement in thermal stability compared to R31. Furthermore, combining the G176K mutation with V231C/Y250C further enhanced both productivity and anti-fibrotic activity. These findings suggest that the enhanced stability of domain IIIA, conferred by V231C/Y250C, along with the increased rigidity of the RBP/IIIA interface, optimizes interdomain distance and alignment, facilitating proper protein folding.
Collapse
Affiliation(s)
- Myungho Sohn
- New Drug Development Center, Osong Medical Innovation Foundation, Osong 28160, Republic of Korea; (M.S.); (S.K.); (H.J.J.); (I.Y.K.)
| | - Sanggil Kim
- New Drug Development Center, Osong Medical Innovation Foundation, Osong 28160, Republic of Korea; (M.S.); (S.K.); (H.J.J.); (I.Y.K.)
| | - Hyeon Ju Jeong
- New Drug Development Center, Osong Medical Innovation Foundation, Osong 28160, Republic of Korea; (M.S.); (S.K.); (H.J.J.); (I.Y.K.)
| | - In Young Ko
- New Drug Development Center, Osong Medical Innovation Foundation, Osong 28160, Republic of Korea; (M.S.); (S.K.); (H.J.J.); (I.Y.K.)
| | - Ji Wook Moon
- Department of Biomedical Sciences, College of Medicine, Korea University, Seoul 02841, Republic of Korea; (J.W.M.); (D.L.)
| | - Dowon Lee
- Department of Biomedical Sciences, College of Medicine, Korea University, Seoul 02841, Republic of Korea; (J.W.M.); (D.L.)
| | - Junseo Oh
- Department of Biomedical Sciences, College of Medicine, Korea University, Seoul 02841, Republic of Korea; (J.W.M.); (D.L.)
| |
Collapse
|
17
|
Zhang Y, Li L, Dong L, Cheng Y, Huang X, Xue B, Jiang C, Cao Y, Yang J. Hydrogel-Based Strategies for Liver Tissue Engineering. CHEM & BIO ENGINEERING 2024; 1:887-915. [PMID: 39975572 PMCID: PMC11835278 DOI: 10.1021/cbe.4c00079] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/14/2024] [Revised: 09/15/2024] [Accepted: 09/15/2024] [Indexed: 02/21/2025]
Abstract
The liver's role in metabolism, detoxification, and immune regulation underscores the urgency of addressing liver diseases, which claim millions of lives annually. Due to donor shortages in liver transplantation, liver tissue engineering (LTE) offers a promising alternative. Hydrogels, with their biocompatibility and ability to mimic the liver's extracellular matrix (ECM), support cell survival and function in LTE. This review analyzes recent advances in hydrogel-based strategies for LTE, including decellularized liver tissue hydrogels, natural polymer-based hydrogels, and synthetic polymer-based hydrogels. These materials are ideal for in vitro cell culture and obtaining functional hepatocytes. Hydrogels' tunable properties facilitate creating artificial liver models, such as organoids, 3D bioprinting, and liver-on-a-chip technologies. These developments demonstrate hydrogels' versatility in advancing LTE's applications, including hepatotoxicity testing, liver tissue regeneration, and treating acute liver failure. This review highlights the transformative potential of hydrogels in LTE and their implications for future research and clinical practice.
Collapse
Affiliation(s)
- Yu Zhang
- National
Laboratory of Solid State Microstructures, Department of Physics, Nanjing University, Nanjing 210093, China
- Jinan
Microecological Biomedicine Shandong Laboratory, Jinan 250021, China
| | - Luofei Li
- National
Laboratory of Solid State Microstructures, Department of Physics, Nanjing University, Nanjing 210093, China
| | - Liang Dong
- National
Laboratory of Solid State Microstructures, Department of Physics, Nanjing University, Nanjing 210093, China
| | - Yuanqi Cheng
- National
Laboratory of Solid State Microstructures, Department of Physics, Nanjing University, Nanjing 210093, China
| | - Xiaoyu Huang
- National
Laboratory of Solid State Microstructures, Department of Physics, Nanjing University, Nanjing 210093, China
| | - Bin Xue
- National
Laboratory of Solid State Microstructures, Department of Physics, Nanjing University, Nanjing 210093, China
| | - Chunping Jiang
- Jinan
Microecological Biomedicine Shandong Laboratory, Jinan 250021, China
| | - Yi Cao
- National
Laboratory of Solid State Microstructures, Department of Physics, Nanjing University, Nanjing 210093, China
- Jinan
Microecological Biomedicine Shandong Laboratory, Jinan 250021, China
| | - Jiapeng Yang
- National
Laboratory of Solid State Microstructures, Department of Physics, Nanjing University, Nanjing 210093, China
- Jinan
Microecological Biomedicine Shandong Laboratory, Jinan 250021, China
| |
Collapse
|
18
|
Li X, Feng J, Cheng H, Jin N, Jin S, Liu Z, Xu J, Xie J. Human umbilical cord mesenchymal stem cells enhance liver regeneration and decrease collagen content in fibrosis mice after partial hepatectomy by activating Wnt/β-catenin signaling. Acta Biochim Biophys Sin (Shanghai) 2024. [PMID: 39716885 DOI: 10.3724/abbs.2024207] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2024] Open
Abstract
Liver fibrosis is a critical stage in the progression of various chronic liver diseases to cirrhosis and liver cancer. Early inhibition of liver fibrosis is crucial for the treatment of liver disease. Hepatectomy, a common treatment for liver-related diseases, promotes liver regeneration. However, in the context of liver fibrosis, liver regeneration is hindered. Many studies have shown that mesenchymal stem cells (MSCs) can promote liver regeneration after partial hepatectomy (PH). However, there are few reports on the impact of MSC therapy on liver regeneration post-PH in the context of hepatic fibrosis. The objective of this study is to examine the impact of MSCs on liver regeneration following PH in the fibrotic liver and uncover the related molecular mechanisms. This study reveals that MSC therapy significantly enhances liver function and mitigates liver inflammation after PH in the context of hepatic fibrosis. MSCs also significantly promote liver regeneration and alleviate liver fibrosis. In addition, this study identifies the role of MSCs in promoting liver regeneration and alleviating liver fibrosis via the activation of Wnt/β-catenin signaling. The combination of MSCs with hepatectomy may offer a novel approach for the treatment of liver fibrotic diseases.
Collapse
Affiliation(s)
- Xuewei Li
- Department of Biochemistry and Molecular Biology, Shanxi Key Laboratory of Birth Defect and Cell Regeneration, MOE Key Laboratory of Coal Environmental Pathogenicity and Prevention, Shanxi Medical University, Taiyuan 030001, China
| | - Jinghui Feng
- Academy of Medical Sciences, Shanxi Medical University, Taiyuan 030001, China
| | - Haiqin Cheng
- Department of Biochemistry and Molecular Biology, Shanxi Key Laboratory of Birth Defect and Cell Regeneration, MOE Key Laboratory of Coal Environmental Pathogenicity and Prevention, Shanxi Medical University, Taiyuan 030001, China
| | - Ning Jin
- Department of Biochemistry and Molecular Biology, Shanxi Key Laboratory of Birth Defect and Cell Regeneration, MOE Key Laboratory of Coal Environmental Pathogenicity and Prevention, Shanxi Medical University, Taiyuan 030001, China
| | - Shanshan Jin
- Department of Biochemistry and Molecular Biology, Shanxi Key Laboratory of Birth Defect and Cell Regeneration, MOE Key Laboratory of Coal Environmental Pathogenicity and Prevention, Shanxi Medical University, Taiyuan 030001, China
| | - Zhizhen Liu
- Department of Biochemistry and Molecular Biology, Shanxi Key Laboratory of Birth Defect and Cell Regeneration, MOE Key Laboratory of Coal Environmental Pathogenicity and Prevention, Shanxi Medical University, Taiyuan 030001, China
| | - Jun Xu
- Department of Hepatobiliary and Pancreatic Surgery and Liver Transplant Center, the First Hospital of Shanxi Medical University, Taiyuan 030001, China
| | - Jun Xie
- Department of Biochemistry and Molecular Biology, Shanxi Key Laboratory of Birth Defect and Cell Regeneration, MOE Key Laboratory of Coal Environmental Pathogenicity and Prevention, Shanxi Medical University, Taiyuan 030001, China
| |
Collapse
|
19
|
Wang S, Gao J, Yang M, Zhang G, Yin L, Tong X. OPN-Mediated Crosstalk Between Hepatocyte E4BP4 and Hepatic Stellate Cells Promotes MASH-Associated Liver Fibrosis. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2024; 11:e2405678. [PMID: 39473081 DOI: 10.1002/advs.202405678] [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] [Received: 05/23/2024] [Revised: 08/06/2024] [Indexed: 12/19/2024]
Abstract
Stressed hepatocytes promote liver fibrosis through communications with hepatic stellate cells (HSCs) during chronic liver injury. However, intra-hepatocyte players that facilitate such cell-to-cell communications are largely undefined. It is previously reported that hepatocyte E4BP4 is potently induced by ER stress and hepatocyte deletion of E4bp4 protects mice from high-fat diet-induced liver steatosis. Here how hepatocyte E4bp4 deficiency impacts the activation of HSCs and the progression toward MASH-associated liver fibrosis is examined. Hepatic E4BP4 is increased in mouse models of NASH diet- or CCl4-induced liver fibrosis. Hepatocyte-specific E4bp4 deletion protected mice against NASH diet-induced liver injury, inflammation, and fibrosis without impacting liver steatosis. Hepatocyte E4BP4 overexpression activated HSCs in a medium transfer experiment, whereas hepatocyte E4bp4 depletion did the opposite. RNA-Seq analysis identified the pro-fibrogenic factor OPN as a critical target of E4BP4 within hepatocytes. Antibody neutralization or shRNA depletion of Opn abrogated hepatocyte E4BP4-induced HSC activation. E4BP4 interacted with and stabilized YAP, an established activator of OPN. Loss of hepatic Yap blocked OPN induction in the liver of Ad-E4bp4-injected mice. Hepatocyte E4BP4 induces OPN via YAP to activate HSCs and promote liver fibrosis during diet-induced MASH. Inhibition of the hepatocyte E4BP4-OPN pathway could offer a novel therapeutic avenue for treating MASLD/MASH.
Collapse
Affiliation(s)
- Sujuan Wang
- Department of Infectious Diseases, The Second Xiangya Hospital, Central South University, 139 Renmin Middle Rd, Furong District, Changsha, Hunan, 410011, P. R. China
| | - Jiashi Gao
- Department of Infectious Diseases, The Second Xiangya Hospital, Central South University, 139 Renmin Middle Rd, Furong District, Changsha, Hunan, 410011, P. R. China
- Department of Molecular & Integrative Physiology, University of Michigan Medical School, NCRC 20-3843, 2800 Plymouth Road, Ann Arbor, MI, 48105, USA
- Caswell Diabetes Institute, University of Michigan Medical School, NCRC 20-3843, 2800 Plymouth Road, Ann Arbor, MI, 48105, USA
| | - Meichan Yang
- Department of Radiology, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, 106 Zhongshan 2nd Road, Guangzhou, Guangdong, 51008, P. R. China
- Provincial Key Laboratory of Artificial Intelligence in Medical Image Analysis and Application, Guangzhou, Guangdong, 51008, P. R. China
| | - Gary Zhang
- Department of Molecular & Integrative Physiology, University of Michigan Medical School, NCRC 20-3843, 2800 Plymouth Road, Ann Arbor, MI, 48105, USA
- Caswell Diabetes Institute, University of Michigan Medical School, NCRC 20-3843, 2800 Plymouth Road, Ann Arbor, MI, 48105, USA
| | - Lei Yin
- Department of Molecular & Integrative Physiology, University of Michigan Medical School, NCRC 20-3843, 2800 Plymouth Road, Ann Arbor, MI, 48105, USA
- Caswell Diabetes Institute, University of Michigan Medical School, NCRC 20-3843, 2800 Plymouth Road, Ann Arbor, MI, 48105, USA
| | - Xin Tong
- Department of Molecular & Integrative Physiology, University of Michigan Medical School, NCRC 20-3843, 2800 Plymouth Road, Ann Arbor, MI, 48105, USA
- Caswell Diabetes Institute, University of Michigan Medical School, NCRC 20-3843, 2800 Plymouth Road, Ann Arbor, MI, 48105, USA
| |
Collapse
|
20
|
Nesci A, Ruggieri V, Manilla V, Spinelli I, Santoro L, Di Giorgio A, Santoliquido A, Ponziani FR. Endothelial Dysfunction and Liver Cirrhosis: Unraveling of a Complex Relationship. Int J Mol Sci 2024; 25:12859. [PMID: 39684569 DOI: 10.3390/ijms252312859] [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: 09/27/2024] [Revised: 11/22/2024] [Accepted: 11/27/2024] [Indexed: 12/18/2024] Open
Abstract
Endothelial dysfunction (ED) is the in the background of multiple metabolic diseases and a key process in liver disease progression and cirrhosis decompensation. ED affects liver sinusoidal endothelial cells (LSECs) in response to different damaging agents, causing their progressive dedifferentiation, unavoidably associated with an increase in intrahepatic resistance that leads to portal hypertension and hyperdynamic circulation with increased cardiac output and low peripheral artery resistance. These changes are driven by a continuous interplay between different hepatic cell types, invariably leading to increased reactive oxygen species (ROS) formation, increased release of pro-inflammatory cytokines and chemokines, and reduced nitric oxide (NO) bioavailability, with a subsequent loss of proper vascular tone regulation and fibrosis development. ED evaluation is often accomplished by serum markers and the flow-mediated dilation (FMD) measurement of the brachial artery to assess its NO-dependent response to shear stress, which usually decreases in ED. In the context of liver cirrhosis, the ED assessment could help understand the complex hemodynamic changes occurring in the early and late stages of the disease. However, the instauration of a hyperdynamic state and the different NO bioavailability in intrahepatic and systemic circulation-often defined as the NO paradox-must be considered confounding factors during FMD analysis. The primary purpose of this review is to describe the main features of ED and highlight the key findings of the dynamic and intriguing relationship between ED and liver disease. We will also focus on the significance of FMD evaluation in this setting, pointing out its key role as a therapeutic target in the never-ending battle against liver cirrhosis progression.
Collapse
Affiliation(s)
- Antonio Nesci
- Angiology and Noninvasive Vascular Diagnostics Unit, Department of Cardiovascular Sciences, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy
| | - Vittorio Ruggieri
- Angiology and Noninvasive Vascular Diagnostics Unit, Department of Cardiovascular Sciences, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy
| | - Vittoria Manilla
- Liver Unit, CEMAD-Centro Malattie dell'Apparato Digerente, Medicina Interna e Gastroenterologia, Fondazione Policlinico Universitario Gemelli IRCCS, 00168 Rome, Italy
| | - Irene Spinelli
- Liver Unit, CEMAD-Centro Malattie dell'Apparato Digerente, Medicina Interna e Gastroenterologia, Fondazione Policlinico Universitario Gemelli IRCCS, 00168 Rome, Italy
| | - Luca Santoro
- Angiology and Noninvasive Vascular Diagnostics Unit, Department of Cardiovascular Sciences, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy
| | - Angela Di Giorgio
- Angiology and Noninvasive Vascular Diagnostics Unit, Department of Cardiovascular Sciences, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy
| | - Angelo Santoliquido
- Angiology and Noninvasive Vascular Diagnostics Unit, Department of Cardiovascular Sciences, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy
- Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
| | - Francesca Romana Ponziani
- Liver Unit, CEMAD-Centro Malattie dell'Apparato Digerente, Medicina Interna e Gastroenterologia, Fondazione Policlinico Universitario Gemelli IRCCS, 00168 Rome, Italy
- Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
| |
Collapse
|
21
|
Yamagata K, Takasuga S, Tatematsu M, Fuchimukai A, Yamada T, Mizuno M, Morii M, Ebihara T. FoxD1 expression identifies a distinct subset of hepatic stellate cells involved in liver fibrosis. Biochem Biophys Res Commun 2024; 734:150632. [PMID: 39226736 DOI: 10.1016/j.bbrc.2024.150632] [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: 08/28/2024] [Accepted: 08/29/2024] [Indexed: 09/05/2024]
Abstract
Hepatic stellate cells (HSCs) are pericytes of the liver responsible for liver fibrosis and cirrhosis, which are the end stages of chronic liver diseases. TGF-β activates HSCs, leading to the differentiation of myofibroblasts in the process of liver fibrosis. While the heterogeneity of HSCs is appreciated in the fibrotic liver, it remains elusive which HSC subsets mainly contribute to fibrosis. Here, we show that the expression of the pericyte marker FoxD1 specifically marks a subset of HSCs in FoxD1-fate tracer mice. HSCs fate-mapped by FoxD1 were preferentially localized in the portal and peripheral areas of both the homeostatic and fibrotic liver induced by carbon tetrachloride. Furthermore, the deletion of Cbfβ, which is necessary for TGF-β signaling, in FoxD1-expressing cells ameliorated liver fibrosis. Thus, we identified an HSC subset that preferentially responds to liver injuries.
Collapse
Affiliation(s)
- Kenki Yamagata
- Department of Medical Biology, Akita University Graduate School of Medicine, Akita, 0108543, Japan; Department of Pediatric Surgery, Akita University Graduate School of Medicine, Akita, 0108543, Japan
| | - Shunsuke Takasuga
- Department of Medical Biology, Akita University Graduate School of Medicine, Akita, 0108543, Japan
| | - Megumi Tatematsu
- Department of Medical Biology, Akita University Graduate School of Medicine, Akita, 0108543, Japan
| | - Akane Fuchimukai
- Department of Medical Biology, Akita University Graduate School of Medicine, Akita, 0108543, Japan
| | - Toshiki Yamada
- Department of Otorhinolaryngology, Head and Neck Surgery, Akita University Graduate School of Medicine, Akita, 0108543, Japan
| | - Masaru Mizuno
- Department of Pediatric Surgery, Akita University Graduate School of Medicine, Akita, 0108543, Japan
| | - Mayako Morii
- Department of Pediatric Surgery, Akita University Graduate School of Medicine, Akita, 0108543, Japan.
| | - Takashi Ebihara
- Department of Medical Biology, Akita University Graduate School of Medicine, Akita, 0108543, Japan; Center for Integrated Control, Epidemiology and Molecular Pathophysiology of Infectious Diseases, Akita University, Akita, 0108543, Japan.
| |
Collapse
|
22
|
Kao C, Ho CH. Time-course RNA sequencing reveals high similarity in mRNAome between hepatic stellate cells activated by agalactosyl IgG and TGF-β1. Funct Integr Genomics 2024; 24:215. [PMID: 39549087 DOI: 10.1007/s10142-024-01502-z] [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: 09/13/2024] [Revised: 11/12/2024] [Accepted: 11/13/2024] [Indexed: 11/18/2024]
Abstract
Previous studies have demonstrated the clinical relevance of aberrant serum immunoglobulin G (IgG) N-glycomic profiles in liver fibrosis and the pathogenic effects of agalactosyl IgG on activating hepatic stellate cells (HSCs). However, the dynamics of gene expression changes during HSC activation by agalactosyl IgG remain poorly understood. We performed RNA sequencing to analyze the mRNAome of human LX-2 HSCs at multiple time points after treatment with agalactosyl IgG and then compared these results with those obtained after normal IgG and transforming growth factor (TGF)-β1 treatments. Gene expression changes were significantly pronounced on day 5 and subsided by day 11 after HSC activation. A high degree of similarity in gene expression patterns between HSCs treated with agalactosyl IgG and TGF-β1 was observed, of which 1796 and 1785 differentially expressed genes (DEGs) were identified, respectively. Disease ontology analyses revealed that 114 and 105 DEGs in activated HSCs following agalactosyl IgG and TGF-β1 treatments, respectively, were linked to liver cirrhosis, hepatitis, fatty liver disease, hepatitis B, and alcoholic hepatitis, with CCL5 and FAS being the most commonly affected genes. DEGs associated with liver fibrosis or aforementioned liver diseases involved in gene annotation, physiological functions, and signaling pathways regarding secretion of cytokines and chemokines, expression of fibrosis-related growth factors and their receptors, modification of extracellular matrices, and regulation of cell viability in activated HSCs. In conclusion, this study characterized the dynamics of mRNAome and gene networks and identified the liver fibrosis-related DEGs during HSC activation by agalactosyl IgG and TGF-β1.
Collapse
Affiliation(s)
- Chieh Kao
- Department of Medical Laboratory Science, College of Medical Science and Technology, I-Shou University, No.8, Yida Road, Jiaosu Village, Yanchao District, Kaohsiung City, 82445, Taiwan
- School of Medicine for International Students, I-Shou University, Kaohsiung, Taiwan
| | - Cheng-Hsun Ho
- Department of Medical Laboratory Science, College of Medical Science and Technology, I-Shou University, No.8, Yida Road, Jiaosu Village, Yanchao District, Kaohsiung City, 82445, Taiwan.
| |
Collapse
|
23
|
Wang Y, Leaker B, Qiao G, Sojoodi M, Eissa IR, Epstein ET, Eddy J, Dimowo O, Lauer GM, Qadan M, Lanuti M, Chung RT, Fuchs BC, Tanabe KK. Precision-cut liver slices as an ex vivo model to evaluate antifibrotic therapies for liver fibrosis and cirrhosis. Hepatol Commun 2024; 8:e0558. [PMID: 39445861 PMCID: PMC11512631 DOI: 10.1097/hc9.0000000000000558] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/22/2024] [Accepted: 07/24/2024] [Indexed: 10/25/2024] Open
Abstract
BACKGROUND Considering the lack of successful treatment options and poor prognosis for cirrhosis and cirrhosis-induced HCC, new platforms to investigate antifibrotic therapies are urgently needed. Precision-cut liver slice (PCLS) is a powerful ex vivo culture model that can supplement and potentially replace the traditional models. METHODS PCLS were prepared from 4 different murine cirrhotic models (choline-deficient, l-amino acid-defined, high-fat diet, thioacetamide, diethylnitrosamine, and carbon tetrachloride) and compared with in vivo murine experiments, in vitro hepatic stellate cells, and human cirrhotic PCLS. RESULTS PCLS viability in culture was stable for 72 hours. Treatment of erlotinib, an EGF receptor inhibitor, significantly inhibited profibrogenic gene expressions in PCLS from choline-deficient, l-amino acid-defined, high-fat diet or thioacetamide-induced cirrhotic rats. Erlotinib treatment of PCLS from diethylnitrosamine or carbon tetrachloride-induced cirrhotic rats inhibited the expression of profibrogenic genes, which was consistent with the impact of erlotinib on these genes in in vivo diethylnitrosamine or carbon tetrachloride-induced cirrhosis. In addition, in hepatic stellate cells at PCLS from normal mice, erlotinib treatment inhibited TGF-β1-upregulated expression of Acta2. Similar expression results were observed in in vitro hepatic stellate cells. Expression of key regulators of fibrosis progression and regression were also significantly altered. Changes in profibrogenic gene expression under erlotinib treatment were also corroborated with human cirrhotic PCLS. CONCLUSIONS Responses to antifibrotic interventions can be detected and quantified with PCLS at the gene expression level. The antifibrotic effects of erlotinib are consistent between PCLS models of murine cirrhosis and those observed in vivo and in vitro. These results were verified in human cirrhotic PCLS. PCLS is an excellent model for assessing antifibrotic therapies that are aligned with the principles of replacement, reduction, and refinement (3Rs), and it will benefit preclinical and clinical research for human fibrosis and cirrhosis.
Collapse
Affiliation(s)
- Yongtao Wang
- Division of Gastrointestinal and Oncologic Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA
- Liver Center, Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA
| | - Ben Leaker
- Wellman Center for Photomedicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA
- Harvard-MIT program in Health Sciences and Technology, Massachusetts Institute of Technology, Boston, Massachusetts, USA
| | - Guoliang Qiao
- Division of Gastrointestinal and Oncologic Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA
| | - Mozhdeh Sojoodi
- Division of Gastrointestinal and Oncologic Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA
| | - Ibrahim Ragab Eissa
- Division of Gastrointestinal and Oncologic Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA
| | - Eliana T. Epstein
- Liver Center, Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA
| | - Jonathan Eddy
- Liver Center, Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA
| | - Oizoshimoshiofu Dimowo
- Liver Center, Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA
| | - Georg M. Lauer
- Liver Center, Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA
| | - Motaz Qadan
- Division of Gastrointestinal and Oncologic Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA
| | - Michael Lanuti
- Division of Thoracic Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA
| | - Raymond T. Chung
- Liver Center, Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA
| | - Bryan C. Fuchs
- Division of Gastrointestinal and Oncologic Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA
| | - Kenneth K. Tanabe
- Division of Gastrointestinal and Oncologic Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA
| |
Collapse
|
24
|
Sekar V, VP V, Vijay V, BR A, Vijayan N, Perumal MK. Inhibition of hepatic stellate cell activation by nutraceuticals: an emphasis on mechanisms of action. JOURNAL OF FOOD SCIENCE AND TECHNOLOGY 2024; 61:2046-2056. [PMID: 39397845 PMCID: PMC11464960 DOI: 10.1007/s13197-024-06002-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Revised: 05/01/2024] [Accepted: 05/07/2024] [Indexed: 10/15/2024]
Abstract
Liver diseases emerge as a serious threat to humans worldwide due to increasing morbidity and mortality. Liver disease related deaths accounts for one third of all disease related death globally. A simple fatty liver if unattended advances further to liver fibrosis, cirrhosis and hepatocellular carcinoma. During liver fibrogenesis, hepatic stellate cells gets activated into myofibroblast like cells and exhibit proliferative and fibrogenic features. Targeting these activated hepatic stellate cells offer promising therapeutic approach towards liver fibrosis management. To date there is no Food and Drug Administration approved treatments for liver fibrosis. However, a large number of clinical trials are being conducted employing monoclonal antibodies, drugs, dietary supplements and herbal medicines. A vast number of research findings demonstrated nutraceuticals to be effective against experimental liver fibrosis both in vitro and in vivo. Nutraceuticals typically regulate key signaling pathways in activated hepatic stellate cells and exhibit anti-fibrotic effect. In this review, the mechanistic action of nutraceuticals targeting activated hepatic stellate cells were summarized to establish them as a possible therapeutic candidate for liver fibrosis.
Collapse
Affiliation(s)
- Vasudevan Sekar
- Department of Biochemistry, CSIR-Central Food Technological Research Institute, Mysore, Karnataka 570020 India
| | - Venkateish VP
- Department of Biochemistry, CSIR-Central Food Technological Research Institute, Mysore, Karnataka 570020 India
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002 India
| | - Vani Vijay
- Department of Biochemistry, CSIR-Central Food Technological Research Institute, Mysore, Karnataka 570020 India
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002 India
| | - Annapoorna BR
- Department of Biochemistry, CSIR-Central Food Technological Research Institute, Mysore, Karnataka 570020 India
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002 India
| | - Nivya Vijayan
- Department of Biochemistry, CSIR-Central Food Technological Research Institute, Mysore, Karnataka 570020 India
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002 India
| | - Madan Kumar Perumal
- Department of Biochemistry, CSIR-Central Food Technological Research Institute, Mysore, Karnataka 570020 India
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002 India
| |
Collapse
|
25
|
Li S, Cheng F, Zhang Z, Xu R, Shi H, Yan Y. The role of hepatocyte-derived extracellular vesicles in liver and extrahepatic diseases. Biomed Pharmacother 2024; 180:117502. [PMID: 39357327 DOI: 10.1016/j.biopha.2024.117502] [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: 07/21/2024] [Revised: 09/09/2024] [Accepted: 09/19/2024] [Indexed: 10/04/2024] Open
Abstract
Extracellular vesicles (EVs) are vesicle-like bodies with a double membrane structure that are released from the cell membrane or secreted by cells into the extracellular environment. These include exosomes, microvesicles, and apoptotic bodies. There is growing evidence indicating that the composition of liver cell contents changes following injury. The quantity of EVs and the biologically active substances they carry vary depending on the condition of the liver cells. Hepatocytes utilize EVs to modulate the functions of different liver cells and transfer them to distant organs via the systemic circulation, thereby playing a crucial role in intercellular communication. This review provides a concise overview of the research on the effects and potential mechanisms of hepatocyte-derived EVs (Hep-EVs) on liver diseases and extrahepatic diseases under different physiological and pathological conditions. Common liver diseases discussed include non-alcoholic fatty liver disease (NAFLD), viral hepatitis, alcoholic liver disease, drug-induced liver damage, and liver cancer. Given that NAFLD is the most prevalent chronic liver disease globally, this review particularly highlights the use of hepatocyte-derived EVs in NAFLD for disease progression, diagnosis, and treatment.
Collapse
Affiliation(s)
- Shihui Li
- Department of Laboratory Medicine, Wujin Hospital Affiliated with Jiangsu University, Changzhou 213017, China; Department of Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang 212013, China
| | - Fang Cheng
- Department of Laboratory Medicine, Wujin Hospital Affiliated with Jiangsu University, Changzhou 213017, China; Department of Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang 212013, China
| | - Zhuan Zhang
- Department of Laboratory Medicine, Wujin Hospital Affiliated with Jiangsu University, Changzhou 213017, China; Department of Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang 212013, China
| | - Ruizi Xu
- Department of Laboratory Medicine, Wujin Hospital Affiliated with Jiangsu University, Changzhou 213017, China; Department of Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang 212013, China
| | - Honglei Shi
- Wujin Hospital Affiliated With Jiangsu University, Changzhou Wujin People's Hospital, Changzhou Medical Center, Nanjing Medical University, Changzhou 213004, China; Changzhou Key Laboratory of Molecular Diagnostics and Precision Cancer Medicine, Wujin Hospital Affiliated with Jiangsu University (Wujin Clinical College of Xuzhou Medical University), Changzhou 213017, China; Wujin Institute of Molecular Diagnostics and Precision Cancer Medicine of Jiangsu University, Changzhou 213017, China.
| | - Yongmin Yan
- Department of Laboratory Medicine, Wujin Hospital Affiliated with Jiangsu University, Changzhou 213017, China; Changzhou Key Laboratory of Molecular Diagnostics and Precision Cancer Medicine, Wujin Hospital Affiliated with Jiangsu University (Wujin Clinical College of Xuzhou Medical University), Changzhou 213017, China; Wujin Institute of Molecular Diagnostics and Precision Cancer Medicine of Jiangsu University, Changzhou 213017, China.
| |
Collapse
|
26
|
Castanho Martins M, Dixon ED, Lupo G, Claudel T, Trauner M, Rombouts K. Role of PNPLA3 in Hepatic Stellate Cells and Hepatic Cellular Crosstalk. Liver Int 2024. [PMID: 39394864 DOI: 10.1111/liv.16117] [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: 08/29/2024] [Revised: 09/16/2024] [Accepted: 09/17/2024] [Indexed: 10/14/2024]
Abstract
AIMS Since its discovery, the patatin-like phospholipase domain containing 3 (PNPLA3) (rs738409 C>G p.I148M) variant has been studied extensively to unravel its molecular function. Although several studies proved a causal relationship between the PNPLA3 I148M variant and MASLD development and particularly fibrosis, the pathological mechanisms promoting this phenotype have not yet been fully clarified. METHODS We summarise the latest data regarding the PNPLA3 I148M variant in hepatic stellate cells (HSCs) activation and macrophage biology or the path to inflammation-induced fibrosis. RESULTS Elegant but contradictory studies have ascribed PNPLA3 a hydrolase or an acyltransferase function. The PNPLA3 I148M results in hepatic lipid accumulation, which predisposes the hepatocyte to lipotoxicity and lipo-apoptosis, producing DAMPs, cytokines and chemokines leading to recruitment and activation of macrophages and HSCs, propagating fibrosis. Recent studies showed that the PNPLA3 I148M variant alters HSCs biology via attenuation of PPARγ, AP-1, LXRα and TGFβ activity and signalling. CONCLUSIONS The advent of refined techniques in isolating HSCs has made PNPLA3's direct role in HSCs for liver fibrosis development more apparent. However, many other mechanisms still need detailed investigations.
Collapse
Affiliation(s)
- Maria Castanho Martins
- Regenerative Medicine and Fibrosis Group, Institute for Liver and Digestive Health, University College London, Royal Free Campus, London, UK
| | - Emmanuel Dauda Dixon
- Hans Popper Laboratory of Molecular Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - Giulia Lupo
- Regenerative Medicine and Fibrosis Group, Institute for Liver and Digestive Health, University College London, Royal Free Campus, London, UK
| | - Thierry Claudel
- Hans Popper Laboratory of Molecular Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - Michael Trauner
- Hans Popper Laboratory of Molecular Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - Krista Rombouts
- Regenerative Medicine and Fibrosis Group, Institute for Liver and Digestive Health, University College London, Royal Free Campus, London, UK
| |
Collapse
|
27
|
Niu C, Zhang J, Okolo PI. The possible pathogenesis of liver fibrosis: therapeutic potential of natural polyphenols. Pharmacol Rep 2024; 76:944-961. [PMID: 39162986 DOI: 10.1007/s43440-024-00638-w] [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: 03/13/2024] [Revised: 08/08/2024] [Accepted: 08/09/2024] [Indexed: 08/21/2024]
Abstract
Liver fibrosis is the formation of a fibrous scar resulting from chronic liver injury, independently from etiology. Although many of the mechanical details remain unknown, activation of hepatic stellate cells (HSCs) is a central driver of liver fibrosis. Extracellular mechanisms such as apoptotic bodies, paracrine stimuli, inflammation, and oxidative stress are critical in activating HSCs. The potential for liver fibrosis to reverse after removing the causative agent has heightened interest in developing antifibrotic therapies. Polyphenols, the secondary plant metabolites, have gained attention because of their health-beneficial properties, including well-recognized antioxidant and anti-inflammatory activities, in the setting of liver fibrosis. In this review, we present an overview of the mechanisms underlying liver fibrosis with a specific focus on the activation of resident HSCs. We highlight the therapeutic potential and promising role of natural polyphenols to mitigate liver fibrosis pathogenesis, focusing on HSCs activation. We also discuss the translational gap from preclinical findings to clinical treatments involved in natural polyphenols in liver fibrosis.
Collapse
Affiliation(s)
- Chengu Niu
- Internal medicine residency program, Rochester General Hospital, 1425 Portland Avenue, Rochester, NY, 14621, USA.
| | - Jing Zhang
- Rainier Springs Behavioral Health Hospital, 2805 NE 129th St, Vancouver, WA, 98686, USA
| | - Patrick I Okolo
- Division of Gastroenterology, Rochester General Hospital, Rochester, NY, 14621, USA
| |
Collapse
|
28
|
Jeong M, Shin S, Lee G, Lee Y, Park SB, Kang J, Lee YS, Seo W, Lee H. Engineered lipid nanoparticles enable therapeutic gene silencing of GTSE1 for the treatment of liver fibrosis. J Control Release 2024; 374:337-348. [PMID: 39154935 DOI: 10.1016/j.jconrel.2024.08.012] [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: 06/16/2024] [Revised: 07/26/2024] [Accepted: 08/08/2024] [Indexed: 08/20/2024]
Abstract
Liver fibrosis is characterized by abnormal accumulation of extracellular matrix proteins, disrupting normal liver function. Despite its significant health impact, effective treatments remain limited. Here, we present the development of engineered lipid nanoparticles (LNPs) for targeted RNA therapeutic delivery in the liver. We investigated the therapeutic potential of modulating the G2 and S-phase expressed 1 (GTSE1) protein for treating liver fibrosis. Through screening, we identified P138Y LNP as a potent candidate with superior delivery efficiency and lower toxicity. Using these engineered LNPs, we successfully delivered siGTSE1 to hepatocytes, significantly reducing collagen accumulation and restoring liver function in a fibrosis animal model. Additionally, GTSE1 downregulation altered miRNA expression and upregulated hepatocyte nuclear factor 4 alpha (HNF4α). These findings suggest that therapeutic gene silencing of GTSE1 is a promising strategy for treating liver fibrosis by regenerating liver phenotypes and functions.
Collapse
Affiliation(s)
- Michaela Jeong
- College of Pharmacy, Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul 03760, Republic of Korea
| | - Sumin Shin
- College of Pharmacy, Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul 03760, Republic of Korea
| | - Gyeongseok Lee
- College of Pharmacy, Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul 03760, Republic of Korea
| | - Yeji Lee
- College of Pharmacy, Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul 03760, Republic of Korea
| | - Seo Bhin Park
- College of Pharmacy, Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul 03760, Republic of Korea
| | - Jisoo Kang
- College of Pharmacy, Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul 03760, Republic of Korea
| | - Young-Sun Lee
- Department of Internal Medicine, Korea University Medical Center, Seoul 08308, Republic of Korea
| | - Wonhyo Seo
- College of Pharmacy, Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul 03760, Republic of Korea.
| | - Hyukjin Lee
- College of Pharmacy, Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul 03760, Republic of Korea.
| |
Collapse
|
29
|
Ye L, Huang J, Liang X, Guo W, Sun X, Shao C, He Y, Zhang J. Jiawei Taohe Chengqi Decoction attenuates CCl 4 induced hepatic fibrosis by inhibiting HSCs activation via TGF-β1/CUGBP1 and IFN-γ/Smad7 pathway. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2024; 133:155916. [PMID: 39094440 DOI: 10.1016/j.phymed.2024.155916] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/26/2024] [Revised: 05/20/2024] [Accepted: 07/25/2024] [Indexed: 08/04/2024]
Abstract
BACKGROUND Hepatic fibrosis (HF) is an essential stage in the progression of different chronic liver conditions to cirrhosis and even hepatocellular carcinoma. The activation of hepatic stellate cells (HSCs) plays a crucial role in the progression of HF. IFN- γ/Smad7 pathway can inhibit HSCs activation, while TGF-β1/CUGBP1 pathway can inhibit IFN-γ/Smad7 pathway transduction and promote HSCs activation. Thus, inhibiting the TGF-β1/CUGBP1 pathway and activating the IFN-γ/Smad7 pathway reverses HSCs activation and inhibits HF. Jiawei Taohe Chengqi Decoction (JTCD) was derived from the Taohe Chengqi Tang in the ancient Chinese medical text titled "Treatise on Febrile Diseases". We found several anti-HF components in JTCD including ginsenoside Rb1 and others, but the specific mechanism of anti-HF in JTCD is not clear. PURPOSE To elucidate the specific mechanism by which JTCD reverses HF by inhibiting the activation of HSCs, and to establish a scientific foundation for treating HF with Traditional Chinese medicine (TCM). METHODS We constructed a CCl4-induced mice HF model in vivo and activated human hepatic stellate cell line (LX-2) with TGF-β1 in vitro, after which they were treated with JTCD and the corresponding inhibitors. We examined the expression of pivotal molecules in the two pathways mentioned above by immunofluorescence staining, Western blotting and RT-PCR. RESULTS JTCD attenuated liver injury and reduced serum ALT and AST levels in mice. In addition, JTCD attenuated CCl4-induced HF by decreasing the expression of α-SMA, COL1A1 and other markers of HSCs activation in mice liver tissue. Moreover, JTCD effectively suppressed the levels of TGF-β1, p-Smad3, p-p38MAPK, p-ATF2, and CUGBP1 in vivo and in vitro and upregulated the levels of IFN-γ, p-STAT1, and Smad7. Mechanically, after using the inhibitors of both pathways in vitro, we found that JTCD inhibited the activation of HSCs by restoring the balance of the TGF-β1/CUGBP1 and IFN-γ/Smad7 pathways. CONCLUSION We demonstrated that JTCD inhibited HSCs activation and reversed HF by inhibiting the TGF-β1/CUGBP1 signalling pathway and upregulating the IFN-γ/Smad7 signalling pathway. Moreover, we have identified specific links where JTCD interferes with both pathways to inhibit HSCs activation. JTCD is an effective candidate for the clinical treatment of HF.
Collapse
Affiliation(s)
- Linmao Ye
- School of Basic Medical Sciences, Zhejiang Chinese Medical University, No. 548 Binwen Road, Binjiang District, Hangzhou 310053, China
| | - Jiaxin Huang
- School of Basic Medical Sciences, Zhejiang Chinese Medical University, No. 548 Binwen Road, Binjiang District, Hangzhou 310053, China
| | - Xiaofan Liang
- School of Basic Medical Sciences, Zhejiang Chinese Medical University, No. 548 Binwen Road, Binjiang District, Hangzhou 310053, China
| | - Wenqin Guo
- School of Basic Medical Sciences, Zhejiang Chinese Medical University, No. 548 Binwen Road, Binjiang District, Hangzhou 310053, China
| | - Xiguang Sun
- School of Basic Medical Sciences, Zhejiang Chinese Medical University, No. 548 Binwen Road, Binjiang District, Hangzhou 310053, China
| | - Chang Shao
- School of Basic Medical Sciences, Zhejiang Chinese Medical University, No. 548 Binwen Road, Binjiang District, Hangzhou 310053, China
| | - Yi He
- School of Basic Medical Sciences, Zhejiang Chinese Medical University, No. 548 Binwen Road, Binjiang District, Hangzhou 310053, China
| | - Junjie Zhang
- School of Basic Medical Sciences, Zhejiang Chinese Medical University, No. 548 Binwen Road, Binjiang District, Hangzhou 310053, China.
| |
Collapse
|
30
|
Baj J, Kołodziej M, Kobak J, Januszewski J, Syty K, Portincasa P, Forma A. Significance of Immune and Non-Immune Cell Stroma as a Microenvironment of Hepatocellular Carcinoma-From Inflammation to Hepatocellular Carcinoma Progression. Int J Mol Sci 2024; 25:10233. [PMID: 39408564 PMCID: PMC11475949 DOI: 10.3390/ijms251910233] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2024] [Revised: 09/19/2024] [Accepted: 09/20/2024] [Indexed: 10/20/2024] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common liver cancer as well as the most prevalent cause of death in the adult patient population with cirrhosis. The occurrence of HCC is primarily caused by chronic liver inflammation that might occur because of a viral infection, non-alcoholic fatty liver disease (NAFLD), or various lifestyle-associated factors. The objective of this review was to summarize the current knowledge regarding the microenvironment of HCC, indicating how immune- and non-immune-cell stroma might affect the onset and progression of HCC. Therefore, in the following narrative review, we described the role of tumor-infiltrating neutrophils, bone-marrow-derived cells, tumor-associated mast cells, cancer-associated fibroblasts, tumor-associated macrophages, liver-sinusoidal endothelial cells, lymphocytes, and certain cytokines in liver inflammation and the further progression to HCC. A better understanding of the HCC microenvironment might be crucial to introducing novel treatment strategies or combined therapies that could lead to more effective clinical outcomes.
Collapse
Affiliation(s)
- Jacek Baj
- Department of Correct, Clinical and Imaging Anatomy, Chair of Fundamental Sciences, Medical University of Lublin, Jaczewskiego 4, 20-090 Lublin, Poland; (J.B.); (J.J.)
| | - Magdalena Kołodziej
- Chair and Department of Forensic Medicine, Medical University of Lublin, Jaczewskiego 8b, 20-090 Lublin, Poland; (M.K.); (J.K.)
| | - Joanna Kobak
- Chair and Department of Forensic Medicine, Medical University of Lublin, Jaczewskiego 8b, 20-090 Lublin, Poland; (M.K.); (J.K.)
| | - Jacek Januszewski
- Department of Correct, Clinical and Imaging Anatomy, Chair of Fundamental Sciences, Medical University of Lublin, Jaczewskiego 4, 20-090 Lublin, Poland; (J.B.); (J.J.)
| | - Kinga Syty
- Institute of Health Sciences, John Paul the II Catholic University of Lublin, Konstantynów 1G, 20-708 Lublin, Poland;
| | - Piero Portincasa
- Clinica Medica “A. Murri”, Department of Biomedical Sciences & Human Oncology, University of Bari Medical School, 70124 Bari, Italy;
| | - Alicja Forma
- Chair and Department of Forensic Medicine, Medical University of Lublin, Jaczewskiego 8b, 20-090 Lublin, Poland; (M.K.); (J.K.)
| |
Collapse
|
31
|
Zhang Y, Ren L, Tian Y, Guo X, Wei F, Zhang Y. Signaling pathways that activate hepatic stellate cells during liver fibrosis. Front Med (Lausanne) 2024; 11:1454980. [PMID: 39359922 PMCID: PMC11445071 DOI: 10.3389/fmed.2024.1454980] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2024] [Accepted: 08/26/2024] [Indexed: 10/04/2024] Open
Abstract
Liver fibrosis is a complex process driven by various factors and is a key feature of chronic liver diseases. Its essence is liver tissue remodeling caused by excessive accumulation of collagen and other extracellular matrix. Activation of hepatic stellate cells (HSCs), which are responsible for collagen production, plays a crucial role in promoting the progression of liver fibrosis. Abnormal expression of signaling pathways, such as the TGF-β/Smads pathway, contributes to HSCs activation. Recent studies have shed light on these pathways, providing valuable insights into the development of liver fibrosis. Here, we will review six signaling pathways such as TGF-β/Smads that have been studied more in recent years.
Collapse
Affiliation(s)
- Youtian Zhang
- The Second Hospital of Lanzhou University, Lanzhou, China
- The Department of General Surgery, The Second Hospital of Lanzhou University, Lanzhou, China
- The Laboratory of Hepatic-Biliary-Pancreatic, The Second Hospital of Lanzhou University, Lanzhou, China
| | - Long Ren
- The Second Hospital of Lanzhou University, Lanzhou, China
- The Department of General Surgery, The Second Hospital of Lanzhou University, Lanzhou, China
- The Laboratory of Hepatic-Biliary-Pancreatic, The Second Hospital of Lanzhou University, Lanzhou, China
| | - Yinting Tian
- The Second Hospital of Lanzhou University, Lanzhou, China
- The Department of General Surgery, The Second Hospital of Lanzhou University, Lanzhou, China
- The Laboratory of Hepatic-Biliary-Pancreatic, The Second Hospital of Lanzhou University, Lanzhou, China
| | - Xiaohu Guo
- The Second Hospital of Lanzhou University, Lanzhou, China
- The Department of General Surgery, The Second Hospital of Lanzhou University, Lanzhou, China
- The Laboratory of Hepatic-Biliary-Pancreatic, The Second Hospital of Lanzhou University, Lanzhou, China
| | - Fengxian Wei
- The Second Hospital of Lanzhou University, Lanzhou, China
- The Department of General Surgery, The Second Hospital of Lanzhou University, Lanzhou, China
- The Laboratory of Hepatic-Biliary-Pancreatic, The Second Hospital of Lanzhou University, Lanzhou, China
| | - Yawu Zhang
- The Second Hospital of Lanzhou University, Lanzhou, China
- The Department of General Surgery, The Second Hospital of Lanzhou University, Lanzhou, China
- The Laboratory of Hepatic-Biliary-Pancreatic, The Second Hospital of Lanzhou University, Lanzhou, China
| |
Collapse
|
32
|
Guo Q, Yang A, Zhao R, Zhao H, Mu Y, Zhang J, Han Q, Su Y. Nimodipine ameliorates liver fibrosis via reshaping liver immune microenvironment in TAA-induced in mice. Int Immunopharmacol 2024; 138:112586. [PMID: 38955030 DOI: 10.1016/j.intimp.2024.112586] [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: 01/04/2024] [Revised: 06/24/2024] [Accepted: 06/26/2024] [Indexed: 07/04/2024]
Abstract
Nimodipine, a calcium antagonist, exert beneficial neurovascular protective effects in clinic. Recently, Calcium channel blockers (CCBs) was reported to protect against liver fibrosis in mice, while the exact effects of Nimodipine on liver injury and hepatic fibrosis remain unclear. In this study, we assessed the effect of nimodipine in Thioacetamide (TAA)-induced liver fibrosis mouse model. Then, the collagen deposition and liver inflammation were assessed by HE straining. Also, the frequency and phenotype of NK cells, CD4+T and CD8+T cells and MDSC in liver and spleen were analyzed using flow cytometry. Furthermore, activation and apoptosis of primary Hepatic stellate cells (HSCs) and HSC line LX2 were detected using α-SMA staining and TUNEL assay, respectively. We found that nimodipine administration significantly attenuated liver inflammation and fibrosis. And the increase of the numbers of hepatic NK and NKT cells, a reversed CD4+/CD8+T ratio, and reduced the numbers of MDSC were observed after nimodipine treatment. Furthermore, nimodipine administration significantly decreased α-SMA expression in liver tissues, and increased TUNEL staining adjacent to hepatic stellate cells. Nimodipine also reduced the proliferation of LX2, and significantly promoted high level of apoptosis in vitro. Moreover, nimodipine downregulated Bcl-2 and Bcl-xl, simultaneously increased expression of JNK, p-JNK, and Caspase-3. Together, nimodipine mediated suppression of growth and fibrogenesis of HSCs may warrant its potential use in the treatment of liver fibrosis.
Collapse
Affiliation(s)
- Quanjuan Guo
- Institute of Immunopharmaceutical Sciences, School of Pharmaceutical Sciences, Shandong University, Jinan 250012, Shandong, China
| | - Ailu Yang
- Institute of Immunopharmaceutical Sciences, School of Pharmaceutical Sciences, Shandong University, Jinan 250012, Shandong, China
| | - Rongrong Zhao
- Institute of Immunopharmaceutical Sciences, School of Pharmaceutical Sciences, Shandong University, Jinan 250012, Shandong, China
| | - Huajun Zhao
- Institute of Immunopharmaceutical Sciences, School of Pharmaceutical Sciences, Shandong University, Jinan 250012, Shandong, China
| | - Yongliang Mu
- Institute of Immunopharmaceutical Sciences, School of Pharmaceutical Sciences, Shandong University, Jinan 250012, Shandong, China
| | - Jian Zhang
- Institute of Immunopharmaceutical Sciences, School of Pharmaceutical Sciences, Shandong University, Jinan 250012, Shandong, China
| | - Qiuju Han
- Institute of Immunopharmaceutical Sciences, School of Pharmaceutical Sciences, Shandong University, Jinan 250012, Shandong, China.
| | - Yuhang Su
- Department of Emergency Surgery, Qilu Hospital of Shandong University, Jinan 250012, Shandong, China.
| |
Collapse
|
33
|
Wensveen FM, Šestan M, Polić B. The immunology of sickness metabolism. Cell Mol Immunol 2024; 21:1051-1065. [PMID: 39107476 PMCID: PMC11364700 DOI: 10.1038/s41423-024-01192-4] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2024] [Accepted: 05/29/2024] [Indexed: 09/01/2024] Open
Abstract
Everyone knows that an infection can make you feel sick. Although we perceive infection-induced changes in metabolism as a pathology, they are a part of a carefully regulated process that depends on tissue-specific interactions between the immune system and organs involved in the regulation of systemic homeostasis. Immune-mediated changes in homeostatic parameters lead to altered production and uptake of nutrients in circulation, which modifies the metabolic rate of key organs. This is what we experience as being sick. The purpose of sickness metabolism is to generate a metabolic environment in which the body is optimally able to fight infection while denying vital nutrients for the replication of pathogens. Sickness metabolism depends on tissue-specific immune cells, which mediate responses tailored to the nature and magnitude of the threat. As an infection increases in severity, so do the number and type of immune cells involved and the level to which organs are affected, which dictates the degree to which we feel sick. Interestingly, many alterations associated with metabolic disease appear to overlap with immune-mediated changes observed following infection. Targeting processes involving tissue-specific interactions between activated immune cells and metabolic organs therefore holds great potential for treating both people with severe infection and those with metabolic disease. In this review, we will discuss how the immune system communicates in situ with organs involved in the regulation of homeostasis and how this communication is impacted by infection.
Collapse
Affiliation(s)
| | - Marko Šestan
- University of Rijeka Faculty of Medicine, Rijeka, Croatia
| | - Bojan Polić
- University of Rijeka Faculty of Medicine, Rijeka, Croatia
| |
Collapse
|
34
|
Wang H, Liu J, Zhu P, Shi L, Liu Y, Yang X, Yang X. Single-nucleus transcriptome reveals cell dynamic response of liver during the late chick embryonic development. Poult Sci 2024; 103:103979. [PMID: 38941785 PMCID: PMC11261130 DOI: 10.1016/j.psj.2024.103979] [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: 03/18/2024] [Revised: 05/29/2024] [Accepted: 06/10/2024] [Indexed: 06/30/2024] Open
Abstract
The late embryonic development of the liver, a major metabolic organ, remains poorly characterized at single cell resolution. Here, we used single-nucleus RNA-sequencing (snRNA-seq) to characterize the chicken liver cells at 2 embryonic development time points (E14 and D1). We uncovered 8 cell types including hepatocytes, endothelial cells, hepatic stellate cells, erythrocytes, cholangiocytes, kupffer cells, mesothelial cells, and lymphocytes. And we discovered significant differences in the abundance of different cell types between E14 and D1. Moreover, we characterized the heterogeneity of hepatocytes, endothelial cells, and mesenchymal cells based on the gene regulatory networks of each clusters. Trajectory analyses revealed 128 genes associated with hepatocyte development and function, including apolipoprotein genes involved hepatic lipid metabolism and NADH dehydrogenase subunits involved hepatic oxidative phosphorylation. Furthermore, we identified the differentially expressed genes (DEGs) between E14 and D1 at the cellular levels, which contribute to changes in liver development and function. These DEGs were significantly enriched in PPAR signaling pathways and lipid metabolism related pathways. Our results presented the single-cell mapping of chick embryonic liver at late stages of development and demonstrated the metabolic changes across the 2 age stages at the cellular level, which can help to further study the molecular development mechanism of embryonic liver.
Collapse
Affiliation(s)
- Huimei Wang
- College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi, 712100, PR China
| | - Jiongyan Liu
- College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi, 712100, PR China
| | - Pinhui Zhu
- College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi, 712100, PR China
| | - Lin Shi
- College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi, 712100, PR China
| | - Yanli Liu
- College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi, 712100, PR China
| | - Xiaojun Yang
- College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi, 712100, PR China
| | - Xin Yang
- College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi, 712100, PR China.
| |
Collapse
|
35
|
Miyaaki H, Miuma S, Fukusima M, Sasaki R, Haraguchi M, Nakao Y, Akazawa Y, Nakao K. Liver fibrosis analysis using digital pathology. Med Mol Morphol 2024; 57:161-166. [PMID: 38980407 DOI: 10.1007/s00795-024-00395-y] [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: 04/24/2024] [Accepted: 07/01/2024] [Indexed: 07/10/2024]
Abstract
Digital pathology has enabled the noninvasive quantification of pathological parameters. In addition, the combination of digital pathology and artificial intelligence has enabled the analysis of a vast amount of information, leading to the sharing of much information and the elimination of knowledge gaps. Fibrosis, which reflects chronic inflammation, is the most important pathological parameter in chronic liver diseases, such as viral hepatitis and metabolic dysfunction-associated steatotic liver disease. It has been reported that the quantitative evaluation of various fibrotic parameters by digital pathology can predict the prognosis of liver disease and hepatocarcinogenesis. Liver fibrosis evaluation methods include 1 fiber quantification, 2 elastin and collagen quantification, 3 s harmonic generation/two photon excitation fluorescence (SHG/TPE) microscopy, and 4 Fibronest™.. In this review, we provide an overview of role of digital pathology on the evaluation of fibrosis in liver disease and the characteristics of recent methods to assess liver fibrosis.
Collapse
Affiliation(s)
- Hisamitsu Miyaaki
- Department of Gastroenterology and Hepatology, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki, 852-8501, Japan.
| | - Satoshi Miuma
- Department of Gastroenterology and Hepatology, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki, 852-8501, Japan
| | - Masanori Fukusima
- Department of Gastroenterology and Hepatology, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki, 852-8501, Japan
| | - Ryu Sasaki
- Department of Gastroenterology and Hepatology, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki, 852-8501, Japan
| | - Masafumi Haraguchi
- Department of Gastroenterology and Hepatology, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki, 852-8501, Japan
| | - Yasuhiko Nakao
- Department of Gastroenterology and Hepatology, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki, 852-8501, Japan
| | - Yuko Akazawa
- Department of Gastroenterology and Hepatology, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki, 852-8501, Japan
- Department of Histology and Cell Biology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Kazuhiko Nakao
- Department of Gastroenterology and Hepatology, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki, 852-8501, Japan
| |
Collapse
|
36
|
Mata-Martínez E, Ramírez-Ledesma MG, Vázquez-Victorio G, Hernández-Muñoz R, Díaz-Muñoz M, Vázquez-Cuevas FG. Purinergic Signaling in Non-Parenchymal Liver Cells. Int J Mol Sci 2024; 25:9447. [PMID: 39273394 PMCID: PMC11394727 DOI: 10.3390/ijms25179447] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2024] [Revised: 08/27/2024] [Accepted: 08/29/2024] [Indexed: 09/15/2024] Open
Abstract
Purinergic signaling has emerged as an important paracrine-autocrine intercellular system that regulates physiological and pathological processes in practically all organs of the body. Although this system has been thoroughly defined since the nineties, recent research has made substantial advances regarding its role in aspects of liver physiology. However, most studies have mainly targeted the entire organ, 70% of which is made up of parenchymal cells or hepatocytes. Because of its physiological role, the liver is exposed to toxic metabolites, such as xenobiotics, drugs, and fatty acids, as well as to pathogens such as viruses and bacteria. Under injury conditions, all cell types within the liver undergo adaptive changes. In this context, the concentration of extracellular ATP has the potential to increase dramatically. Indeed, this purinergic response has not been studied in sufficient detail in non-parenchymal liver cells. In the present review, we systematize the physiopathological adaptations related to the purinergic system in chronic liver diseases of non-parenchymal liver cells, such as hepatic stellate cells, Kupffer cells, sinusoidal endothelial cells, and cholangiocytes. The role played by non-parenchymal liver cells in these circumstances will undoubtedly be strategic in understanding the regenerative activities that support the viability of this organ under stressful conditions.
Collapse
Affiliation(s)
- Esperanza Mata-Martínez
- Departamento de Biología Celular y Desarrollo, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México (UNAM), Ciudad Universitaria, Mexico City 04510, Mexico
| | - María Guadalupe Ramírez-Ledesma
- Departamento de Neurobiología Celular y Molecular, Instituto de Neurobiología, Universidad Nacional Autónoma de México (UNAM), Boulevard Juriquilla #3001, Querétaro 76230, Mexico
| | - Genaro Vázquez-Victorio
- Departamento de Física, Facultad de Ciencias, Universidad Nacional Autónoma de México (UNAM), Circuito Exterior S/N, Ciudad Universitaria, Mexico City 04510, Mexico
| | - Rolando Hernández-Muñoz
- Departamento de Biología Celular y Desarrollo, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México (UNAM), Ciudad Universitaria, Mexico City 04510, Mexico
| | - Mauricio Díaz-Muñoz
- Departamento de Neurobiología Celular y Molecular, Instituto de Neurobiología, Universidad Nacional Autónoma de México (UNAM), Boulevard Juriquilla #3001, Querétaro 76230, Mexico
| | - Francisco G Vázquez-Cuevas
- Departamento de Neurobiología Celular y Molecular, Instituto de Neurobiología, Universidad Nacional Autónoma de México (UNAM), Boulevard Juriquilla #3001, Querétaro 76230, Mexico
| |
Collapse
|
37
|
Cholico GN, Nault R, Zacharewski T. Cell-specific AHR-driven differential gene expression in the mouse liver cell following acute TCDD exposure. BMC Genomics 2024; 25:809. [PMID: 39198768 PMCID: PMC11351262 DOI: 10.1186/s12864-024-10730-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2024] [Accepted: 08/21/2024] [Indexed: 09/01/2024] Open
Abstract
2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a persistent environmental contaminant that disrupts hepatic function leading to steatotic liver disease (SLD)-like pathologies, such as steatosis, steatohepatitis, and fibrosis. These effects are mediated by the aryl hydrocarbon receptor following changes in gene expression. Although diverse cell types are involved, initial cell-specific changes in gene expression have not been reported. In this study, differential gene expression in hepatic cell types was examined in male C57BL/6 mice gavaged with 30 µg/kg of TCDD using single-nuclei RNA-sequencing. Ten liver cell types were identified with the proportions of most cell types remaining unchanged, except for neutrophils which increased at 72 h. Gene expression suggests TCDD induced genes related to oxidative stress in hepatocytes as early as 2 h. Lipid homeostasis was disrupted in hepatocytes, macrophages, B cells, and T cells, characterized by the induction of genes associated with lipid transport, steroid hormone biosynthesis, and the suppression of β-oxidation, while linoleic acid metabolism was altered in hepatic stellate cells (HSCs), B cells, portal fibroblasts, and plasmacytoid dendritic cells. Pro-fibrogenic processes were also enriched, including the induction retinol metabolism genes in HSCs and the early induction of anti-fibrolysis genes in hepatocytes, endothelial cells, HSCs, and macrophages. Hepatocytes also had gene expression changes consistent with hepatocellular carcinoma. Collectively, these findings underscore the effects of TCDD in initiating SLD-like phenotypes and identified cell-specific gene expression changes related to oxidative stress, steatosis, fibrosis, cell proliferation and the development of HCC.
Collapse
Affiliation(s)
- Giovan N Cholico
- Biochemistry and Molecular Biology, Michigan State University, East Lansing, Michigan, USA
- Institute for Integrative Toxicology, Michigan State University, East Lansing, Michigan, USA
| | - Rance Nault
- Institute for Integrative Toxicology, Michigan State University, East Lansing, Michigan, USA
- Pharmacology and Toxicology, Michigan State University, East Lansing, Michigan, USA
| | - Tim Zacharewski
- Biochemistry and Molecular Biology, Michigan State University, East Lansing, Michigan, USA.
- Institute for Integrative Toxicology, Michigan State University, East Lansing, Michigan, USA.
| |
Collapse
|
38
|
He X, Sun Z, Sun J, Chen Y, Luo Y, Wang Z, Linghu D, Song M, Cao C. Single-cell transcriptomics reveal the microenvironment landscape of perfluorooctane sulfonate-induced liver injury in female mice. THE SCIENCE OF THE TOTAL ENVIRONMENT 2024; 940:173562. [PMID: 38825197 DOI: 10.1016/j.scitotenv.2024.173562] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/30/2024] [Revised: 05/08/2024] [Accepted: 05/25/2024] [Indexed: 06/04/2024]
Abstract
Epidemic and animal studies have reported that perfluoroalkyl and polyfluoroalkyl substances (PFASs) are strongly associated with liver injury; however, to date, the effects of PFASs on the hepatic microenvironment remain largely unknown. In this study, we established perfluorooctane sulfonic acid (PFOS)-induced liver injury models by providing male and female C57BL/6 mice with water containing PFOS at varying doses for 4 weeks. Hematoxylin and eosin staining revealed that PFOS induced liver injury in both sexes. Elevated levels of serum aminotransferases including those of alanine aminotransferase and aspartate transaminase were detected in the serum of mice treated with PFOS. Female mice exhibited more severe liver injury than male mice. We collected the livers from female mice and performed single-cell RNA sequencing. In total, 36,529 cells were included and grouped into 10 major cell types: B cells, granulocytes, T cells, NK cells, monocytes, dendritic cells, macrophages, endothelial cells, fibroblasts, and hepatocytes. Osteoclast differentiation was upregulated and the T cell receptor signaling pathway was significantly downregulated in PFOS-treated livers. Further analyses revealed that among immune cell clusters in PFOS-treated livers, Tcf7+CD4+T cells were predominantly downregulated, whereas conventional dendritic cells and macrophages were upregulated. Among the fibroblast subpopulations, hepatic stellate cells were significantly enriched in PFOS-treated female mice. CellphoneDB analysis suggested that fibroblasts interact closely with endothelial cells. The major ligand-receptor pairs between fibroblasts and endothelial cells in PFOS-treated livers were Dpp4_Cxcl12, Ackr3_Cxcl12, and Flt1_complex_Vegfa. These genes are associated with directing cell migration and angiogenesis. Our study provides a general framework for understanding the microenvironment in the livers of female mice exposed to PFOS at the single-cell level.
Collapse
Affiliation(s)
- Xinrong He
- Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Zhichao Sun
- Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Jingyuan Sun
- Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Yiyao Chen
- Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Yongyi Luo
- Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Zhiyi Wang
- Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Dongli Linghu
- Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Miao Song
- Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Chuanhui Cao
- Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China; Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Guangzhou, Guangdong, China.
| |
Collapse
|
39
|
Monti F, Perazza F, Leoni L, Stefanini B, Ferri S, Tovoli F, Zavatta G, Piscaglia F, Petroni ML, Ravaioli F. RANK-RANKL-OPG Axis in MASLD: Current Evidence Linking Bone and Liver Diseases and Future Perspectives. Int J Mol Sci 2024; 25:9193. [PMID: 39273141 PMCID: PMC11395242 DOI: 10.3390/ijms25179193] [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: 08/22/2024] [Accepted: 08/22/2024] [Indexed: 09/15/2024] Open
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD)-and its worse form, metabolic-associated steatohepatitis (MASH), characterised by inflammation and liver damage-corresponds to the liver's involvement in metabolic syndrome, which constitutes an economic burden for healthcare systems. However, the biomolecular pathways that contribute to steatotic liver disease are not completely clear. Abnormalities of bone metabolism are frequent in people affected by metabolic liver disease, with reduced bone density and an increased risk of fracture. Receptor activator of NF-κB (RANK), receptor activator of NF-κB ligand (RANKL), and osteoprotegerin(OPG) are critical regulators of bone metabolism, performing pleiotropic effects, and may have potential involvement in metabolic disorders like MASLD, resulting in a topic of great interest and intrigue. This narrative review aims to investigate this potential role and its implications in MASLD development and progression and in hepatocellular carcinoma, which represents its worst complication.
Collapse
Affiliation(s)
- Federico Monti
- Department of Medical and Surgical Sciences, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy
| | - Federica Perazza
- Department of Medical and Surgical Sciences, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy
| | - Laura Leoni
- Department of Dietetics and Clinical Nutrition, Maggiore-Bellaria Hospital, Azienda Unità Sanitaria Locale (AUSL), 40138 Bologna, Italy
| | - Bernardo Stefanini
- Department of Medical and Surgical Sciences, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy
- Division of Internal Medicine, Hepatobiliary and Immunoallergic Diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy
| | - Silvia Ferri
- Division of Internal Medicine, Hepatobiliary and Immunoallergic Diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy
| | - Francesco Tovoli
- Department of Medical and Surgical Sciences, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy
- Division of Internal Medicine, Hepatobiliary and Immunoallergic Diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy
| | - Guido Zavatta
- Department of Medical and Surgical Sciences, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy
- Division of Endocrinology and Diabetes Prevention and Care, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy
| | - Fabio Piscaglia
- Department of Medical and Surgical Sciences, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy
- Division of Internal Medicine, Hepatobiliary and Immunoallergic Diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy
| | - Maria Letizia Petroni
- Department of Medical and Surgical Sciences, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy
- Unit of Clinical Nutrition and Metabolism, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy
| | - Federico Ravaioli
- Department of Medical and Surgical Sciences, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy
- Division of Internal Medicine, Hepatobiliary and Immunoallergic Diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy
| |
Collapse
|
40
|
Breitkopf-Heinlein K, Martinez-Chantar ML. Targeting hepatic stellate cells to combat liver fibrosis: where do we stand? Gut 2024; 73:1411-1413. [PMID: 38684236 DOI: 10.1136/gutjnl-2023-331785] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/25/2024] [Accepted: 04/16/2024] [Indexed: 05/02/2024]
Affiliation(s)
- Katja Breitkopf-Heinlein
- Department of Surgery, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Baden-Württemberg, Germany
| | | |
Collapse
|
41
|
Gao R, Mao J. Noncoding RNA-Mediated Epigenetic Regulation in Hepatic Stellate Cells of Liver Fibrosis. Noncoding RNA 2024; 10:44. [PMID: 39195573 DOI: 10.3390/ncrna10040044] [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: 05/22/2024] [Revised: 07/09/2024] [Accepted: 08/01/2024] [Indexed: 08/29/2024] Open
Abstract
Liver fibrosis is a significant contributor to liver-related disease mortality on a global scale. Despite this, there remains a dearth of effective therapeutic interventions capable of reversing this condition. Consequently, it is imperative that we gain a comprehensive understanding of the underlying mechanisms driving liver fibrosis. In this regard, the activation of hepatic stellate cells (HSCs) is recognized as a pivotal factor in the development and progression of liver fibrosis. The role of noncoding RNAs (ncRNAs) in epigenetic regulation of HSCs transdifferentiation into myofibroblasts has been established, providing new insights into gene expression changes during HSCs activation. NcRNAs play a crucial role in mediating the epigenetics of HSCs, serving as novel regulators in the pathogenesis of liver fibrosis. As research on epigenetics expands, the connection between ncRNAs involved in HSCs activation and epigenetic mechanisms becomes more evident. These changes in gene regulation have attracted considerable attention from researchers in the field. Furthermore, epigenetics has contributed valuable insights to drug discovery and the identification of therapeutic targets for individuals suffering from liver fibrosis and cirrhosis. As such, this review offers a thorough discussion on the role of ncRNAs in the HSCs activation of liver fibrosis.
Collapse
Affiliation(s)
- Ruoyu Gao
- Department of Gastroenterology, First Affiliated Hospital of Dalian Medical University, Dalian 116011, China
| | - Jingwei Mao
- Department of Gastroenterology, First Affiliated Hospital of Dalian Medical University, Dalian 116011, China
| |
Collapse
|
42
|
Wang D, He R, Song Q, Diao H, Jin Y, Zhang A. Calcitriol Inhibits NaAsO 2 Triggered Hepatic Stellate Cells Activation and Extracellular Matrix Oversecretion by Activating Nrf2 Signaling Pathway Through Vitamin D Receptor. Biol Trace Elem Res 2024; 202:3601-3613. [PMID: 37968493 DOI: 10.1007/s12011-023-03957-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/07/2023] [Accepted: 11/08/2023] [Indexed: 11/17/2023]
Abstract
Previous studies, including our own, have demonstrated that arsenic exposure can induce liver fibrosis, while the underlying mechanism remains unclear and there is currently no effective pharmacological intervention available. Recent research has demonstrated that vitamin D supplementation can ameliorate liver fibrosis caused by various etiologies, potentially through modulation of the Nrf2 signaling pathways. However, it remains unclear whether vitamin D intervention can mitigate arsenic-caused liver fibrosis. As is known hepatic stellate cells (HSCs) activation and extracellular matrix (ECM) deposition are pivotal in the pathogenesis of liver fibrosis. In this study, we investigated the intervention effect of calcitriol (a form of active vitamin D) on arsenite-triggered Lx-2 cells (a human hepatic stellate cell line) activation and ECM oversecretion. Additionally, we also elucidated the role and mechanism of Nrf2 antioxidant signaling pathway. Our results demonstrated that calcitriol intervention significantly inhibits Lx-2 cell activation and ECM oversecretion induced by arsenite exposure. Additionally, calcitriol activates Nrf2 and its downstream antioxidant enzyme expression in Lx-2 cells, thereby reducing ROS overproduction caused by arsenite exposure. Further investigation reveals that calcitriol activates the Nrf2 signaling pathway and inhibits arsenite-triggered Lx-2 cell activation and ECM oversecretion by targeting vitamin D receptor (VDR). In conclusion, this study has demonstrated that vitamin D intervention can effectively inhibit HSC activation and ECM oversecretion triggered by arsenite exposure through its antioxidant activity. This provides a novel strategy for targeted nutritional intervention in the treatment of arsenic-induced liver fibrosis.
Collapse
Affiliation(s)
- Dapeng Wang
- Key Laboratory of Environmental Pollution Monitoring and Disease Control, Ministry of Education, School of Public Health, Guizhou Medical University, Guiyang, 550025, Guizhou, People's Republic of China.
- Collaborative Innovation Center for Prevention and Control of Endemic and Ethnic Regional Diseases Co-Constructed By the Province and Ministry, Guizhou Medical University, Guiyang, 550025, Guizhou, People's Republic of China.
| | - Rui He
- Key Laboratory of Environmental Pollution Monitoring and Disease Control, Ministry of Education, School of Public Health, Guizhou Medical University, Guiyang, 550025, Guizhou, People's Republic of China
| | - Qian Song
- Key Laboratory of Environmental Pollution Monitoring and Disease Control, Ministry of Education, School of Public Health, Guizhou Medical University, Guiyang, 550025, Guizhou, People's Republic of China
| | - Heng Diao
- Key Laboratory of Environmental Pollution Monitoring and Disease Control, Ministry of Education, School of Public Health, Guizhou Medical University, Guiyang, 550025, Guizhou, People's Republic of China
| | - Ying Jin
- Key Laboratory of Environmental Pollution Monitoring and Disease Control, Ministry of Education, School of Public Health, Guizhou Medical University, Guiyang, 550025, Guizhou, People's Republic of China
| | - Aihua Zhang
- Key Laboratory of Environmental Pollution Monitoring and Disease Control, Ministry of Education, School of Public Health, Guizhou Medical University, Guiyang, 550025, Guizhou, People's Republic of China.
- Collaborative Innovation Center for Prevention and Control of Endemic and Ethnic Regional Diseases Co-Constructed By the Province and Ministry, Guizhou Medical University, Guiyang, 550025, Guizhou, People's Republic of China.
| |
Collapse
|
43
|
Huang P, Xu J, Jiang S, Zhang Y, Wang X, Xiong C, Xia C. The impact of ICOSL/ICOS pathway-regulated long non-coding RNAs on liver fibrosis in mice infected with Schistosoma japonicum. Parasit Vectors 2024; 17:317. [PMID: 39044218 PMCID: PMC11267842 DOI: 10.1186/s13071-024-06399-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2024] [Accepted: 07/08/2024] [Indexed: 07/25/2024] Open
Abstract
BACKGROUND The primary pathogenic mechanism of schistosomiasis-associated liver fibrosis involves the deposition of schistosome eggs, leading to the formation of liver egg granulomas and subsequent liver fibrosis. Hepatic stellate cells are abnormally activated, resulting in excessive collagen deposition and fibrosis development. While specific long non-coding RNAs (lncRNAs) have been associated with fibrotic processes, their roles in schistosomiasis-associated liver fibrosis remain unclear. METHODS Our previous research indicated that downregulating the ICOSL/ICOS could partially alleviate liver fibrosis. In this study, we established a schistosomiasis infection model in C57BL/6 and ICOSL knockout (KO) mice, and the liver pathology changes were observed at various weeks postinfection (wpi) using hematoxylin and eosin and Masson's trichrome staining. Within the first 4 wpi, no significant liver abnormalities were observed. However, mice exhibited evident egg granulomas and fibrosis in their livers at 7 wpi. Notably, ICOSL-KO mice had significantly smaller pathological variations compared with simultaneously infected C57BL/6 mice. To investigate the impact of lncRNAs on schistosomiasis-associated liver fibrosis, quantitative real-time polymerase chain reaction (RT-qPCR) was used to monitor the dynamic changes of lncRNAs in hepatic stellate cells of infected mice. RESULTS The results demonstrated that lncRNA-H19, -MALAT1, -PVT1, -P21 and -GAS5 all participated in liver fibrosis formation after schistosome infection. In addition, ICOSL-KO mice exhibited significantly inhibited expression of lncRNA-H19, -MALAT1 and -PVT1 after 7 wpi. In contrast, they showed enhanced expression of lncRNA-P21 and -GAS5 compared with C57BL/6 mice, influencing liver fibrosis development. Furthermore, small interfering RNA transfection (siRNA) in JS-1 cells in vitro confirmed that lncRNA-H19, -MALAT1, and -PVT1 promoted liver fibrosis, whereas lncRNA-P21 and -GAS5 had the opposite effect on key fibrotic molecules, including α- smooth muscle actin and collagen I expression. CONCLUSIONS This study uncovers that ICOSL/ICOS may play a role in activating hepatic stellate cells and promoting liver fibrosis in mice infected with Schistosoma japonicum by dynamically regulating the expression of specific lncRNAs. These findings offer potential therapeutic targets for schistosomiasis-associated liver fibrosis.
Collapse
Affiliation(s)
- Ping Huang
- Department of Parasitology, School of Biology & Basic Medical Sciences, Suzhou Medical College of Soochow University, Suzhou, Jiangsu Province, China
- MOE Key Laboratory of Geriatric Diseases and Immunology, Suzhou Key Laboratory of Pathogen Bioscience and Anti-Infective Medicine, School of Biology & Basic Medical Sciences, Suzhou Medical College of Soochow University, Suzhou, Jiangsu Province, China
| | - Jing Xu
- Department of Parasitology, School of Biology & Basic Medical Sciences, Suzhou Medical College of Soochow University, Suzhou, Jiangsu Province, China
- MOE Key Laboratory of Geriatric Diseases and Immunology, Suzhou Key Laboratory of Pathogen Bioscience and Anti-Infective Medicine, School of Biology & Basic Medical Sciences, Suzhou Medical College of Soochow University, Suzhou, Jiangsu Province, China
| | - Suqin Jiang
- Department of Parasitology, School of Biology & Basic Medical Sciences, Suzhou Medical College of Soochow University, Suzhou, Jiangsu Province, China
| | - Yanan Zhang
- Department of Parasitology, School of Biology & Basic Medical Sciences, Suzhou Medical College of Soochow University, Suzhou, Jiangsu Province, China
| | - Xinyi Wang
- Department of Parasitology, School of Biology & Basic Medical Sciences, Suzhou Medical College of Soochow University, Suzhou, Jiangsu Province, China
| | - Chunrong Xiong
- Jiangsu Institute of Parasitic Diseases, Wuxi City, Jiangsu Province, China
| | - Chaoming Xia
- Department of Parasitology, School of Biology & Basic Medical Sciences, Suzhou Medical College of Soochow University, Suzhou, Jiangsu Province, China.
- MOE Key Laboratory of Geriatric Diseases and Immunology, Suzhou Key Laboratory of Pathogen Bioscience and Anti-Infective Medicine, School of Biology & Basic Medical Sciences, Suzhou Medical College of Soochow University, Suzhou, Jiangsu Province, China.
| |
Collapse
|
44
|
Arvanitakis K, Chatzikalil E, Kalopitas G, Patoulias D, Popovic DS, Metallidis S, Kotsa K, Germanidis G, Koufakis T. Metabolic Dysfunction-Associated Steatotic Liver Disease and Polycystic Ovary Syndrome: A Complex Interplay. J Clin Med 2024; 13:4243. [PMID: 39064282 PMCID: PMC11278502 DOI: 10.3390/jcm13144243] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2024] [Revised: 07/17/2024] [Accepted: 07/18/2024] [Indexed: 07/28/2024] Open
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD) and polycystic ovary syndrome (PCOS) are prevalent conditions that have been correlated with infertility through overlapped pathophysiological mechanisms. MASLD is associated with metabolic syndrome and is considered among the major causes of chronic liver disease, while PCOS, which is characterized by ovulatory dysfunction and hyperandrogenism, is one of the leading causes of female infertility. The pathophysiological links between PCOS and MASLD have not yet been fully elucidated, with insulin resistance, hyperandrogenemia, obesity, and dyslipidemia being among the key pathways that contribute to liver lipid accumulation, inflammation, and fibrosis, aggravating liver dysfunction. On the other hand, MASLD exacerbates insulin resistance and metabolic dysregulation in women with PCOS, creating a vicious cycle of disease progression. Understanding the intricate relationship between MASLD and PCOS is crucial to improving clinical management, while collaborative efforts between different medical specialties are essential to optimize fertility and liver health outcomes in individuals with MASLD and PCOS. In this review, we summarize the complex interplay between MASLD and PCOS, highlighting the importance of increasing clinical attention to the prevention, diagnosis, and treatment of both entities.
Collapse
Affiliation(s)
- Konstantinos Arvanitakis
- Division of Gastroenterology and Hepatology, First Department of Internal Medicine, AHEPA University Hospital, Aristotle University of Thessaloniki, St. Kiriakidi 1, 54636 Thessaloniki, Greece; (K.A.); (G.K.); (S.M.); (G.G.)
- Basic and Translational Research Unit, Special Unit for Biomedical Research and Education, School of Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, 54636 Thessaloniki, Greece
| | - Elena Chatzikalil
- Athens Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece;
| | - Georgios Kalopitas
- Division of Gastroenterology and Hepatology, First Department of Internal Medicine, AHEPA University Hospital, Aristotle University of Thessaloniki, St. Kiriakidi 1, 54636 Thessaloniki, Greece; (K.A.); (G.K.); (S.M.); (G.G.)
- Basic and Translational Research Unit, Special Unit for Biomedical Research and Education, School of Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, 54636 Thessaloniki, Greece
| | - Dimitrios Patoulias
- Second Propaedeutic Department of Internal Medicine, Hippokration General Hospital, Aristotle University of Thessaloniki, 54642 Thessaloniki, Greece;
| | - Djordje S. Popovic
- Clinic for Endocrinology, Diabetes and Metabolic Disorders, Clinical Centre of Vojvodina, 21000 Novi Sad, Serbia;
- Medical Faculty, University of Novi Sad, 21000 Novi Sad, Serbia
| | - Symeon Metallidis
- Division of Gastroenterology and Hepatology, First Department of Internal Medicine, AHEPA University Hospital, Aristotle University of Thessaloniki, St. Kiriakidi 1, 54636 Thessaloniki, Greece; (K.A.); (G.K.); (S.M.); (G.G.)
- Division of Endocrinology, First Department of Internal Medicine, AHEPA University Hospital, Aristotle University of Thessaloniki, St. Kiriakidi 1, 54636 Thessaloniki, Greece;
| | - Kalliopi Kotsa
- Division of Endocrinology, First Department of Internal Medicine, AHEPA University Hospital, Aristotle University of Thessaloniki, St. Kiriakidi 1, 54636 Thessaloniki, Greece;
| | - Georgios Germanidis
- Division of Gastroenterology and Hepatology, First Department of Internal Medicine, AHEPA University Hospital, Aristotle University of Thessaloniki, St. Kiriakidi 1, 54636 Thessaloniki, Greece; (K.A.); (G.K.); (S.M.); (G.G.)
- Basic and Translational Research Unit, Special Unit for Biomedical Research and Education, School of Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, 54636 Thessaloniki, Greece
| | - Theocharis Koufakis
- Second Propaedeutic Department of Internal Medicine, Hippokration General Hospital, Aristotle University of Thessaloniki, 54642 Thessaloniki, Greece;
| |
Collapse
|
45
|
Wu S, Li J, Zhan Y. H3K18 lactylation accelerates liver fibrosis progression through facilitating SOX9 transcription. Exp Cell Res 2024; 440:114135. [PMID: 38901791 DOI: 10.1016/j.yexcr.2024.114135] [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: 01/08/2024] [Revised: 06/03/2024] [Accepted: 06/15/2024] [Indexed: 06/22/2024]
Abstract
Liver fibrosis is a significant health concern globally due to its association with severe liver conditions like cirrhosis and liver cancer. Histone lactylation has been implicated in the progression of hepatic fibrosis, but its specific role in liver fibrosis, particularly regarding H3K18 lactylation, remained unclear. To investigate this, we established in vivo and in vitro models of liver fibrosis using carbon tetrachloride (CCl4) injection in rats and stimulation of hepatic stellate cells (HSCs) with TGF-β1, respectively. We found that histone lactylation, particularly H3K18 lactylation, was upregulated in both CCl4-induced rats and TGF-β1-activated HSCs, indicating its potential involvement in liver fibrosis. Further experiments revealed that lactate dehydrogenase A (LDHA) knockdown inhibited H3K18 lactylation and had a beneficial effect on liver fibrosis by suppressing HSC proliferation, migration, and extracellular matrix (ECM) deposition. This suggests that H3K18 lactylation promotes liver fibrosis progression. Chromatin immunoprecipitation (ChIP) and luciferase reporter assays demonstrated that H3K18 lactylation facilitated the transcription of SOX9, a transcription factor associated with fibrosis. Importantly, overexpression of SOX9 counteracted the effects of LDHA silencing on activated HSCs, indicating that SOX9 is downstream of H3K18 lactylation in promoting liver fibrosis. In summary, this study uncovers a novel mechanism by which H3K18 lactylation contributes to liver fibrosis by activating SOX9 transcription. This finding opens avenues for exploring new therapeutic strategies for hepatic fibrosis targeting histone lactylation pathways.
Collapse
Affiliation(s)
- Shujun Wu
- Department of Gastroenterology, The First Hospital of Shanxi Medical University, Taiyuan, Shanxi province 030001, China.
| | - Jianhong Li
- Department of Gastroenterology, The First Hospital of Shanxi Medical University, Taiyuan, Shanxi province 030001, China
| | - Yanfei Zhan
- Department of Gastroenterology, The First Hospital of Shanxi Medical University, Taiyuan, Shanxi province 030001, China
| |
Collapse
|
46
|
Liu XY, Zhang W, Ma BF, Sun MM, Shang QH. Advances in Research on the Effectiveness and Mechanism of Active Ingredients from Traditional Chinese Medicine in Regulating Hepatic Stellate Cells Autophagy Against Hepatic Fibrosis. Drug Des Devel Ther 2024; 18:2715-2727. [PMID: 38974122 PMCID: PMC11227309 DOI: 10.2147/dddt.s467480] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2024] [Accepted: 06/10/2024] [Indexed: 07/09/2024] Open
Abstract
Hepatic fibrosis (HF) is a pathological process of structural and functional impairment of the liver and is a key component in the progression of chronic liver disease. There are no specific anti-hepatic fibrosis (anti-HF) drugs, and HF can only be improved or prevented by alleviating the cause. Autophagy of hepatic stellate cells (HSCs) is closely related to the development of HF. In recent years, traditional Chinese medicine (TCM) has achieved good therapeutic effects in the prevention and treatment of HF. Several active ingredients from TCM (AITCM) can regulate autophagy in HSCs to exert anti-HF effects through different pathways, but relevant reviews are lacking. This paper reviewed the research progress of AITCM regulating HSCs autophagy against HF, and also discussed the relationship between HSCs autophagy and HF, pointing out the problems and limitations of the current study, in order to provide references for the development of anti-HF drugs targeting HSCs autophagy in TCM. By reviewing the literature in PubMed, Web of Science, Embase, CNKI and other databases, we found that the relationship between autophagy of HSCs and HF is currently controversial. HSCs autophagy may promote HF by consuming lipid droplets (LDs) to provide energy for their activation. However, in contrast, inducing autophagy in HSCs can exert the anti-HF effect by stimulating their apoptosis or senescence, reducing type I collagen accumulation, inhibiting the extracellular vesicles release, degrading pro-fibrotic factors and other mechanisms. Some AITCM inhibit HSCs autophagy to resist HF, with the most promising direction being to target LDs. While, others induce HSCs autophagy to resist HF, with the most promising direction being to target HSCs apoptosis. Future research needs to focus on cell targeting research, autophagy targeting research and in vivo verification research, and to explore the reasons for the contradictory effects of HSCs autophagy on HF.
Collapse
Affiliation(s)
- Xin-Yu Liu
- College of First Clinical Medicine, Shandong University of Traditional Chinese Medicine, Jinan, Shandong, 250000, People’s Republic of China
| | - Wei Zhang
- Department of Liver Disease, The 960th Hospital of the PLA Joint Logistics Support Force, Jinan, Shandong, 250000, People’s Republic of China
| | - Bao-Feng Ma
- The third department of encephalopathy, Jinan Integrated Traditional Chinese and Western Medicine Hospital, Jinan, Shandong, 271100, People’s Republic of China
| | - Mi-Mi Sun
- Diagnosis and Treatment Center for Liver Diseases, Tai’an 88 Hospital, Tai’an, Shandong, 271000, People’s Republic of China
| | - Qing-Hua Shang
- Department of Liver Disease, The 960th Hospital of the PLA Joint Logistics Support Force, Jinan, Shandong, 250000, People’s Republic of China
| |
Collapse
|
47
|
Chen CC, Hsu LW, Chen KD, Chiu KW, Kung CP, Li SR, Chen CL, Huang KT. Calreticulin regulates hepatic stellate cell activation through modulating TGF-beta-induced Smad signaling. Cell Calcium 2024; 121:102895. [PMID: 38703416 DOI: 10.1016/j.ceca.2024.102895] [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: 01/26/2024] [Revised: 04/25/2024] [Accepted: 04/27/2024] [Indexed: 05/06/2024]
Abstract
Liver fibrosis is characterized by excessive deposition of extracellular matrix (ECM) as a wound healing process. Activated hepatic stellate cells (HpSCs) are the major producer of the ECM and play a central role in liver fibrogenesis. It has been widely accepted that elimination of activated HpSCs or reversion to a quiescent state can be a feasible strategy for resolving the disease, further highlighting the urgent need for novel therapeutic targets. Calreticulin (CRT) is a molecular chaperone that normally resides in the endoplasmic reticulum (ER), important in protein folding and trafficking through the secretory pathway. CRT also plays a critical role in calcium (Ca2+) homeostasis, with its Ca2+ storage capacity. In the current study, we aimed to demonstrate its function in directing HpSC activation. In a mouse liver injury model, CRT was up-regulated in HpSCs. In cellular experiments, we further showed that this activation was through modulating the canonical TGF-β signaling. As down-regulation of CRT in HpSCs elevated intracellular Ca2+ levels through a form of Ca2+ influx, named store-operated Ca2+ entry (SOCE), we examined whether moderating SOCE affected TGF-β signaling. Interestingly, blocking SOCE had little effect on TGF-β-induced gene expression. In contrast, inhibition of ER Ca2+ release using the inositol trisphosphate receptor inhibitor 2-APB increased TGF-β signaling. Treatment with 2-APB did not alter SOCE but decreased intracellular Ca2+ at the basal level. Indeed, adjusting Ca2+ concentrations by EGTA or BAPTA-AM chelation further enhanced TGF-β-induced signaling. Our results suggest a crucial role of CRT in the liver fibrogenic process through modulating Ca2+ concentrations and TGF-β signaling in HpSCs, which may provide new information and help advance the current discoveries for liver fibrosis.
Collapse
Affiliation(s)
- Chien-Chih Chen
- Department of Psychiatry, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan; School of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Li-Wen Hsu
- Liver Transplantation Center, Department of General Surgery, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan
| | - Kuang-Den Chen
- Liver Transplantation Center, Department of General Surgery, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan; Institute for Translational Research in Biomedicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan
| | - King-Wah Chiu
- Liver Transplantation Center, Department of General Surgery, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan; Division of Hepato-Gastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan
| | - Chao-Pin Kung
- Liver Transplantation Center, Department of General Surgery, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan; Institute for Translational Research in Biomedicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan
| | - Shu-Rong Li
- Liver Transplantation Center, Department of General Surgery, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan
| | - Chao-Long Chen
- Liver Transplantation Center, Department of General Surgery, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan
| | - Kuang-Tzu Huang
- Liver Transplantation Center, Department of General Surgery, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan; Institute for Translational Research in Biomedicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan.
| |
Collapse
|
48
|
Sanfeliu-Redondo D, Gibert-Ramos A, Gracia-Sancho J. Cell senescence in liver diseases: pathological mechanism and theranostic opportunity. Nat Rev Gastroenterol Hepatol 2024; 21:477-492. [PMID: 38485755 DOI: 10.1038/s41575-024-00913-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 02/12/2024] [Indexed: 06/30/2024]
Abstract
The liver is not oblivious to the passage of time, as ageing is a major risk factor for the development of acute and chronic liver diseases. Ageing produces alterations in all hepatic cells, affecting their phenotype and function and worsening the prognosis of liver disease. The ageing process also implies the accumulation of a cellular state characterized by a persistent proliferation arrest and a specific secretory phenotype named cellular senescence. Indeed, senescent cells have key roles in many physiological processes; however, their accumulation owing to ageing or pathological conditions contributes to the damage occurring in chronic diseases. The aim of this Review is to provide an updated description of the pathophysiological events in which hepatic senescent cells are involved and their role in liver disease progression. Finally, we discuss novel geroscience therapies that could be applied to prevent or improve liver diseases and age-mediated hepatic deregulations.
Collapse
Affiliation(s)
- David Sanfeliu-Redondo
- Liver Vascular Biology Laboratory, IDIBAPS Biomedical Research Institute - Hospital Clínic de Barcelona & CIBEREHD, Barcelona, Spain
| | - Albert Gibert-Ramos
- Liver Vascular Biology Laboratory, IDIBAPS Biomedical Research Institute - Hospital Clínic de Barcelona & CIBEREHD, Barcelona, Spain
| | - Jordi Gracia-Sancho
- Liver Vascular Biology Laboratory, IDIBAPS Biomedical Research Institute - Hospital Clínic de Barcelona & CIBEREHD, Barcelona, Spain.
- Department of Visceral Surgery and Medicine, Inselspital - University of Bern, Bern, Switzerland.
| |
Collapse
|
49
|
Wang X, Liu H, Wang Y, Wang P, Yi Y, Lin Y, Li X. Novel protein C6ORF120 promotes liver fibrosis by activating hepatic stellate cells through the PI3K/Akt/mTOR pathway. J Gastroenterol Hepatol 2024; 39:1422-1430. [PMID: 38523410 DOI: 10.1111/jgh.16538] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/16/2023] [Revised: 02/14/2024] [Accepted: 02/27/2024] [Indexed: 03/26/2024]
Abstract
BACKGROUND AND AIM The role of C6ORF120 in promoting CCL4-induced hepatic fibrosis and its possible mechanisms were explored in C6orf120 knockout rats (C6orf120-/-) and LX-2 cells (a type of human hepatic stellate cell line). METHODS In vivo experiments, wild-type and C6orf120-/- rats were used to investigate the function of C6ORF120. In the in vitro experiments, C6ORF120 recombinant protein (rC6ORF120) at a concentration of 200 ng/mL was used to stimulate LX-2 cells. Sirius Red staining, Masson staining, western blotting, polymerase chain reaction, immunohistochemistry, and immunofluorescence were used to explore fibrosis-associated factors. RESULTS C6orf120-/- rats showed mild fibrosis and liver injury in the CCL4-induced liver fibrosis model. Furthermore, RNA-seq revealed that C6orf120-/- rats had less extracellular matrix deposition and activated stellate cells. Consistent with the in vivo, the rC6ORF120 induced LX-2 cell activation. Moreover, mechanistic studies revealed that the p-PI3K/PI3K, p-Akt/Akt, and p-mTOR/mTOR levels were significantly elevated and LY294002 (a PI3K/Akt/mTOR typical pathway inhibitor) reversed the function of C6ORF120 in activating LX-2 cells. CONCLUSION C6ORF120 could activate hepatic stellate cells and promote hepatic fibrosis via the PI3K/Akt/mTOR signaling pathway.
Collapse
Affiliation(s)
- Xin Wang
- Department of Center of Integrated Traditional Chinese and Western Medicine, Peking University Ditan Teaching Hospital, Beijing, China
| | - Hui Liu
- Department of Center of Infectious Disease, Beijing Ditan Hospital; Capital Medical University, Beijing, China
| | - Yuqi Wang
- Department of Center of Integrated Traditional Chinese and Western Medicine, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Peng Wang
- Department of Center of Integrated Traditional Chinese and Western Medicine, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Yunyun Yi
- Department of Center of Integrated Traditional Chinese and Western Medicine, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Yingying Lin
- Department of Center of Integrated Traditional Chinese and Western Medicine, Peking University Ditan Teaching Hospital, Beijing, China
| | - Xin Li
- Department of Center of Integrated Traditional Chinese and Western Medicine, Peking University Ditan Teaching Hospital, Beijing, China
- Department of Center of Integrated Traditional Chinese and Western Medicine, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| |
Collapse
|
50
|
Hagenstein J, Burkhardt S, Sprezyna P, Tasika E, Tiegs G, Diehl L. CD44 expression on murine hepatic stellate cells promotes the induction of monocytic and polymorphonuclear myeloid-derived suppressor cells. J Leukoc Biol 2024; 116:177-185. [PMID: 38484149 DOI: 10.1093/jleuko/qiae053] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2023] [Revised: 01/31/2024] [Accepted: 02/22/2024] [Indexed: 06/30/2024] Open
Abstract
In chronic inflammation, regulatory immune cells, such as regulatory T cells and myeloid-derived suppressor cells, can develop. Local signals in the inflamed tissue, such as cytokines and eicosanoids, but also contact-dependent signals, can promote myeloid-derived suppressor cell development. In the liver, hepatic stellate cells may provide such signals via the expression of CD44. Myeloid-derived suppressor cells generated in the presence of hepatic stellate cells and anti-CD44 antibodies were functionally and phenotypically analyzed. We found that both monocytic and polymorphonuclear myeloid-derived suppressor cells generated in the presence of αCD44 antibodies were less suppressive toward T cells as measured by T-cell proliferation and cytokine production. Moreover, both monocytic and polymorphonuclear myeloid-derived suppressor cells were phenotypically altered. Monocytic myeloid-derived suppressor cells mainly changed their expression of CD80 and CD39, and polymorphonuclear myeloid-derived suppressor cells showed altered expression of CD80/86, PD-L1, and CCR2. Moreover, both polymorphonuclear and monocytic myeloid-derived suppressor cells lost expression of Nos2 messenger RNA, whereas monocytic myeloid-derived suppressor cells showed reduced expression of TGFb messenger RNA and polymorphonuclear myeloid-derived suppressor cells reduced expression of Il10 messenger RNA. In summary, the presence of CD44 in hepatic stellate cells promotes the induction of both monocytic and polymorphonuclear myeloid-derived suppressor cells, although the mechanisms by which these myeloid-derived suppressor cells may increase suppressive function due to interaction with CD44 are only partially overlapping.
Collapse
Affiliation(s)
- Julia Hagenstein
- Institute of Experimental Immunology and Hepatology, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246, Hamburg, Germany
- Hamburg Center of Translational Immunology (HCTI), University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246, Hamburg, Germany
| | - Simon Burkhardt
- Institute of Experimental Immunology and Hepatology, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246, Hamburg, Germany
- Hamburg Center of Translational Immunology (HCTI), University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246, Hamburg, Germany
| | - Paulina Sprezyna
- Institute of Experimental Immunology and Hepatology, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246, Hamburg, Germany
- Hamburg Center of Translational Immunology (HCTI), University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246, Hamburg, Germany
| | - Elena Tasika
- Institute of Experimental Immunology and Hepatology, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246, Hamburg, Germany
- Hamburg Center of Translational Immunology (HCTI), University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246, Hamburg, Germany
| | - Gisa Tiegs
- Institute of Experimental Immunology and Hepatology, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246, Hamburg, Germany
- Hamburg Center of Translational Immunology (HCTI), University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246, Hamburg, Germany
| | - Linda Diehl
- Institute of Experimental Immunology and Hepatology, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246, Hamburg, Germany
- Hamburg Center of Translational Immunology (HCTI), University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246, Hamburg, Germany
| |
Collapse
|