1
|
Jin Z, Cao J, Liu Z, Gao M, Liu H. Comprehensive profiling of candidate biomarkers and immune infiltration landscape in metabolic dysfunction-associated steatohepatitis. Metabol Open 2025; 26:100366. [PMID: 40292075 PMCID: PMC12032907 DOI: 10.1016/j.metop.2025.100366] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2025] [Revised: 04/14/2025] [Accepted: 04/14/2025] [Indexed: 04/30/2025] Open
Abstract
Background The incidence of metabolic dysfunction-associated steatohepatitis (MASH) is increasing, with an incompletely understood pathophysiology involving multiple factors, particularly innate and adaptive immune responses. Given the limited pharmacological treatments available, identification of novel immune metabolic targets is urgently needed. In this study, we aimed to identify hub immune-related genes and potential biomarkers with diagnostic and predictive value for MASH patients. Methods The GSE164760 dataset from the Gene Expression Omnibus was utilized for analysis, and the R package was used to identify differentially expressed genes. Immune-related differentially expressed genes (IR-DEGs) were identified by comparing the overlap of differentially expressed genes with well-known immune-related genes. Furthermore, the biological processes and molecular functions of the IR-DEGs were analyzed. To characterize the hub IR-DEGs, we employed a protein-protein interaction network. The diagnostic and predictive values of these hub IR-DEGs in MASH were confirmed using GSE48452 and GSE63067 datasets. Finally, the significance of the hub IR-DEGs was validated using a mouse model of MASH. Results A total of 91 IR-DEGs were identified, with 61 upregulated and 30 downregulated genes. Based on the protein-protein interaction network, FN1, RHOA, FOS, PDGFRα, CCND1, PIK3R1, CSF1, and FGF3 were identified as the hub IR-DEGs. Moreover, we found that these hub genes are closely correlated with immune cells. Notably, the validation across two independent cohorts as well as a murine MASH model confirmed their high diagnostic potential. Conclusion The hub IR-DEGs, such as FN1, RHOA, FOS, PDGFRα, CCND1, PIK3R1, CSF1, and FGF3, may enhance the diagnosis and prognosis of MASH by modulating immune homeostasis.
Collapse
Affiliation(s)
- Zhangliu Jin
- Department of General Surgery, The Second Affiliated Hospital of Anhui Medical University, Hefei, Anhui, 230601, China
| | - Jianyun Cao
- Reproductive Medicine Center, Xiangya Hospital, Central South University, Changsha, Hunan, 410005, China
| | - Zhaoxun Liu
- Nursing Department, The Third Xiangya Hospital, Central South University, Changsha, Hunan, 410013, China
- Department of Emergency, The Third Xiangya Hospital, Central South University, Changsha, Hunan, 410013, China
| | - Mei Gao
- Department of Pharmacy, Anhui Chest Hospital, Hefei, Anhui, 230000, China
| | - Hailan Liu
- USDA/ARS Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX, 77030, USA
| |
Collapse
|
2
|
Ge Z, Wu Q, Lv C, He Q. The Roles of T Cells in the Development of Metabolic Dysfunction-Associated Steatohepatitis. Immunology 2025. [PMID: 40414629 DOI: 10.1111/imm.13943] [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: 12/04/2024] [Revised: 02/28/2025] [Accepted: 04/28/2025] [Indexed: 05/27/2025] Open
Abstract
Metabolic dysfunction-associated steatohepatitis (MASH), the progressed period of metabolic dysfunction-associated steatotic liver disease (MASLD), is a multifaceted liver disease characterised by inflammation and fibrosis that develops from simple steatosis, even contributing to hepatocellular carcinoma and death. MASH involves several immune cell-mediated inflammation and fibrosis, where T cells play a crucial role through the release of pro-inflammatory cytokines and pro-fibrotic factors. This review discusses the complex role of various T cell subsets in the pathogenesis of MASH and highlights the progress of ongoing clinical trials involving T cell-targeted MASH therapies.
Collapse
Affiliation(s)
- Zhifa Ge
- Department of General Surgery, Nanjing First Hospital, The Affiliated Nanjing Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Qingwei Wu
- Department of General Surgery, Nanjing First Hospital, The Affiliated Nanjing Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Chengyu Lv
- Department of General Surgery, Nanjing First Hospital, The Affiliated Nanjing Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Qifeng He
- Department of General Surgery, Nanjing First Hospital, The Affiliated Nanjing Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| |
Collapse
|
3
|
Dana J, Fattori A, Po C, Beaufrère A, Vilgrain V, Paradis V, Pessaux P, Baumert TF, Gallix B, Venkatasamy A. 7-T MRI-based surrogate for histopathology examination of liver fibrosis. Eur Radiol Exp 2025; 9:54. [PMID: 40410512 PMCID: PMC12102402 DOI: 10.1186/s41747-025-00589-8] [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: 12/05/2024] [Accepted: 04/16/2025] [Indexed: 05/25/2025] Open
Abstract
BACKGROUND To demonstrate that 7-T magnetic resonance imaging (MRI) provides a surrogate for histopathology of fresh ex vivo liver tissue, using the case study of liver fibrosis. METHODS We prospectively enrolled 20 patients undergoing surgical liver resection between November 2021 and April 2023. Each ex vivo fresh liver tissue specimen (~ 1 cm3) was sectioned in half. The first half, stained using Masson's Trichrome and Perls, was assessed by three pathologists using the METAVIR score (reference standard). The second half was imaged with 7-T MRI using a cryoprobe (fat-suppressed T2-weighted turbo/fast spin-echo sequence, spatial resolution 75 × 75 × 200 µm3) and assessed by three radiologists and the same three pathologists, using a newly developed MRI-METAVIR score. RESULTS Five patients were excluded from the final analysis (one patient due to poor specimen quality, two due to surgery cancellation, and two previously published used for reader training). Of the remaining 15 patients, 10 (67%) presented with chronic liver diseases and 8/15 (53%) with advanced (F3 or F4) fibrosis. Radiologists achieved 88% sensitivity, 100% specificity, 93% accuracy (95% confidence interval 68-100%) and 0.94 Harrell's c-index (0.86-1.00). Pathologists achieved 88% sensitivity, 86% specificity, 87% accuracy (60-98%) and 0.87 Harrell's c-index (0.74-0.99). There were no statistically significant differences between MRI-based and pathologic reference standard stage (p ≥ 0.655). CONCLUSION With an in-plane spatial resolution of ~ 75 × 75 µm2, MRI paralleled low-magnification histology, enabling the assessment of micro-architectural liver changes, and provided a surrogate for histopathology examination of fresh ex vivo liver tissue samples at a microscopic level. RELEVANCE STATEMENT 7-T MRI provides a surrogate for histopathology visualisation of fresh ex vivo liver tissue, opening new research perspectives for clinical high-field MRI of the liver. KEY POINTS Using the newly developed MRI-METAVIR score, 7-T MRI data strongly correlated with histopathology, achieving excellent agreement and accuracy. 7-T MRI accurately differentiated advanced from minimal liver fibrosis. 7-T MRI visualises liver micro-architecture, enabling pathology-like, noninvasive three-dimensional imaging.
Collapse
Affiliation(s)
- Jérémy Dana
- Université de Strasbourg, Inserm, UMRS 1110, Institute for Translational Medicine and Liver Disease, Strasbourg, France
- Institute of Image-Guided Surgery - IHU Strasbourg, Strasbourg, France
- Department of Diagnostic Radiology, McGill University, Montreal, Canada
- Augmented Intelligence & Precision Health Laboratory (AIPHL), Research Institute of the McGill University Health Centre, Montreal, Canada
| | - Antonin Fattori
- Département de Pathologie, Hôpitaux Universitaires de Strasbourg, Strasbourg, France
| | - Chrystelle Po
- ICube UMR 7357, Université de Strasbourg/CNRS, Fédération de Médecine Translationnelle de Strasbourg, Strasbourg, France
| | - Aurélie Beaufrère
- Département de Pathologie, Hôpital Beaujon, FHU MOSAIC, Université Paris Cité, Paris, France
| | - Valérie Vilgrain
- Département de Radiologie, Hôpital Beaujon, Université Paris Cité, Paris, France
| | - Valérie Paradis
- Département de Pathologie, Hôpital Beaujon, FHU MOSAIC, Université Paris Cité, Paris, France
| | - Patrick Pessaux
- Université de Strasbourg, Inserm, UMRS 1110, Institute for Translational Medicine and Liver Disease, Strasbourg, France
- Service de Chirurgie Viscérale et Digestive, Nouvel Hôpital Civil, Hôpitaux Universitaires de Strasbourg, Strasbourg, France
| | - Thomas F Baumert
- Université de Strasbourg, Inserm, UMRS 1110, Institute for Translational Medicine and Liver Disease, Strasbourg, France
- Institute of Image-Guided Surgery - IHU Strasbourg, Strasbourg, France
- Pôle Hépato-digestif, Service d'Hépatogastroenterologie, Hôpitaux Universitaires de Strasbourg, Strasbourg, France
| | - Benoît Gallix
- Department of Diagnostic Radiology, McGill University, Montreal, Canada
- Département de Radiologie, Hôpital Américain de Paris, Paris, France
- Inria, Institut national de recherche en sciences et technologies du numérique, Paris, France
| | - Aïna Venkatasamy
- ICube UMR 7357, Université de Strasbourg/CNRS, Fédération de Médecine Translationnelle de Strasbourg, Strasbourg, France.
- Plateforme Imageries du Vivant, Université de Paris, PARCC, INSERM, Paris, France.
- Department of Radiology-Medical Physics, University Hospital Freiburg, Freiburg, Germany.
| |
Collapse
|
4
|
Jee YM, Lee JY, Ryu T. Chronic Inflammation and Immune Dysregulation in Metabolic-Dysfunction-Associated Steatotic Liver Disease Progression: From Steatosis to Hepatocellular Carcinoma. Biomedicines 2025; 13:1260. [PMID: 40427086 PMCID: PMC12109540 DOI: 10.3390/biomedicines13051260] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2025] [Revised: 05/16/2025] [Accepted: 05/19/2025] [Indexed: 05/29/2025] Open
Abstract
Background/Objectives: Metabolic-dysfunction-associated steatotic liver disease (MASLD) progresses from hepatic steatosis to hepatocellular carcinoma (HCC) as a result of systemic immunometabolic dysfunction. This review summarizes the key roles of the innate and adaptive immune mechanisms driving hepatic injury, fibrogenesis, and carcinogenesis in MASLD. Methods: A comprehensive literature review was performed using PubMed to identify relevant published studies. Eligible articles included original research and clinical studies addressing immunological and metabolic mechanisms in MASLD, as well as emerging therapeutic strategies. Results: We highlight the roles of cytokine networks, the gut-liver axis, and immune cell reprogramming. Emerging therapeutic strategies, including cytokine inhibitors, anti-fibrotic agents, metabolic modulators, and nutraceuticals, offer several indications for attenuating MASLD progression and reducing the prevalence of extrahepatic manifestations. Conclusions: Given the heterogeneity of MASLD, personalized combination-based approaches targeting both inflammation and metabolic stress are essential for effective disease management and the prevention of systemic complications.
Collapse
Affiliation(s)
- Young-Min Jee
- Department of Family Medicine, Soonchunhyang University Seoul Hospital, Seoul 04401, Republic of Korea;
- Department of Family Medicine, Graduate School of Medicine, Seoul National University College of Medicine, Seoul 03080, Republic of Korea
| | - Jeong-Yoon Lee
- Department of Neurology, Soonchunhyang University Seoul Hospital, Seoul 04401, Republic of Korea;
- Department of Translational Medicine, Graduate School of Medicine, Seoul National University College of Medicine, Seoul 03080, Republic of Korea
| | - Tom Ryu
- Department of Internal Medicine, Institute for Digestive Research, Digestive Disease Center, Soonchunhyang University College of Medicine, Seoul 04401, Republic of Korea
| |
Collapse
|
5
|
Chu X, Hou Y, Peng C, Li W, Liang M, Mei J, Qian M, Wang J, Xu S, Jiang Y, Wen X, Chen Y, Yuan F, Xie J, Wang C, Zhang J. Exosome-derived miR-548ag drives hepatic lipid accumulation via upregulating FASN through inhibition of DNMT3B. J Lipid Res 2025:100818. [PMID: 40339699 DOI: 10.1016/j.jlr.2025.100818] [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: 01/30/2025] [Revised: 04/26/2025] [Accepted: 04/29/2025] [Indexed: 05/10/2025] Open
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD) is the leading cause of chronic liver disease worldwide. This study investigates the role of serum miR-548ag in regulating lipid metabolism and its contribution to MASLD in obesity. We found that miR-548ag levels were significantly elevated in the serum of both obese and MASLD patients, and positively correlated with body mass index (BMI), fasting plasma glucose (FPG), triglycerides (TG), total cholesterol (TC), LDL, HDL, aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels. Additionally, miR-548ag expression was significantly higher in the liver and abdominal adipose tissue of obese individuals compared to those of normal weight. In vitro studies in HepG2 and L02 cells, along with previous findings, demonstrated that miR-548ag promotes fatty acid synthase (FASN) expression by inhibiting DNA methyltransferase 3B (DNMT3B), thereby enhancing lipid synthesis. This was confirmed in two mouse models: one with tail vein injections of miR-548ag mimic/inhibitor adeno-associated viruses, and another with tail vein injections of exosomes from serum of normal-weight and obese individuals. Both models showed that miR-548ag upregulated FASN through DNMT3B inhibition, leading to increased lipid synthesis and larger hepatic lipid droplets, effects that were reversed by miR-548ag inhibition. Taken together, elevated miR-548ag expression in obesity enhances hepatic lipid synthesis by targeting DNMT3B to upregulate FASN, contributing to the development of MASLD.
Collapse
Affiliation(s)
- Xiaolong Chu
- Medical College of Shihezi University, Bei-Er-Lu, Shihezi, Xinjiang, 832000, China; Department of Medical Genetics , Medical College of Tarim University, 296 Tarim Avenue, Alar, Xinjiang, 843300, China
| | - Yanting Hou
- Medical College of Shihezi University, Bei-Er-Lu, Shihezi, Xinjiang, 832000, China; Laboratory of Xinjiang Endemic and Ethic Diseases, Shihezi University, Shihezi, Xinjiang, 832000, China
| | - Chaoling Peng
- Medical College of Shihezi University, Bei-Er-Lu, Shihezi, Xinjiang, 832000, China; Laboratory of Xinjiang Endemic and Ethic Diseases, Shihezi University, Shihezi, Xinjiang, 832000, China
| | - Wei Li
- First Affiliated Hospital of Shihezi University School of Medicine, Bei-Er-Lu, Shihezi, Xinjiang, 832000, China
| | - Maodi Liang
- Medical College of Shihezi University, Bei-Er-Lu, Shihezi, Xinjiang, 832000, China; Laboratory of Xinjiang Endemic and Ethic Diseases, Shihezi University, Shihezi, Xinjiang, 832000, China
| | - Jin Mei
- Medical College of Shihezi University, Bei-Er-Lu, Shihezi, Xinjiang, 832000, China; Laboratory of Xinjiang Endemic and Ethic Diseases, Shihezi University, Shihezi, Xinjiang, 832000, China
| | - Meiyu Qian
- Medical College of Shihezi University, Bei-Er-Lu, Shihezi, Xinjiang, 832000, China; Laboratory of Xinjiang Endemic and Ethic Diseases, Shihezi University, Shihezi, Xinjiang, 832000, China
| | - Juan Wang
- Medical College of Shihezi University, Bei-Er-Lu, Shihezi, Xinjiang, 832000, China; Laboratory of Xinjiang Endemic and Ethic Diseases, Shihezi University, Shihezi, Xinjiang, 832000, China
| | - Shibo Xu
- Medical College of Shihezi University, Bei-Er-Lu, Shihezi, Xinjiang, 832000, China; Laboratory of Xinjiang Endemic and Ethic Diseases, Shihezi University, Shihezi, Xinjiang, 832000, China
| | - Yidan Jiang
- Medical College of Shihezi University, Bei-Er-Lu, Shihezi, Xinjiang, 832000, China; Laboratory of Xinjiang Endemic and Ethic Diseases, Shihezi University, Shihezi, Xinjiang, 832000, China
| | - Xin Wen
- Medical College of Shihezi University, Bei-Er-Lu, Shihezi, Xinjiang, 832000, China; Laboratory of Xinjiang Endemic and Ethic Diseases, Shihezi University, Shihezi, Xinjiang, 832000, China
| | - Yao Chen
- Medical College of Shihezi University, Bei-Er-Lu, Shihezi, Xinjiang, 832000, China; Laboratory of Xinjiang Endemic and Ethic Diseases, Shihezi University, Shihezi, Xinjiang, 832000, China
| | - Fangyuan Yuan
- Medical College of Shihezi University, Bei-Er-Lu, Shihezi, Xinjiang, 832000, China; Laboratory of Xinjiang Endemic and Ethic Diseases, Shihezi University, Shihezi, Xinjiang, 832000, China
| | - Jianxin Xie
- Medical College of Shihezi University, Bei-Er-Lu, Shihezi, Xinjiang, 832000, China; Department of Medical Genetics , Medical College of Tarim University, 296 Tarim Avenue, Alar, Xinjiang, 843300, China.
| | - Cuizhe Wang
- Medical College of Shihezi University, Bei-Er-Lu, Shihezi, Xinjiang, 832000, China; Laboratory of Xinjiang Endemic and Ethic Diseases, Shihezi University, Shihezi, Xinjiang, 832000, China.
| | - Jun Zhang
- Medical College of Shihezi University, Bei-Er-Lu, Shihezi, Xinjiang, 832000, China; Laboratory of Xinjiang Endemic and Ethic Diseases, Shihezi University, Shihezi, Xinjiang, 832000, China.
| |
Collapse
|
6
|
Keegan A, Malamal G, Lee Y, Korolowicz K, Shepard BD, Ecelbarger CM, Rubiano MM, Avantaggiati ML, Levi M, Rich L, Alfano M, Rosenberg A, Fricke S, Albanese C, Jose J, Rodriguez O. Multimodal Diagnostic Imaging of Metabolic Dysfunction-Associated Steatotic Liver Disease: Noninvasive Analyses by Photoacoustic Ultrasound and Magnetic Resonance Imaging. THE AMERICAN JOURNAL OF PATHOLOGY 2025; 195:875-890. [PMID: 39954964 PMCID: PMC12016859 DOI: 10.1016/j.ajpath.2025.01.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/03/2024] [Revised: 01/14/2025] [Accepted: 01/31/2025] [Indexed: 02/17/2025]
Abstract
Chronic diseases of the liver are major public health concerns worldwide. Steatosis and steatohepatitis associated with alcoholic liver disease, metabolic dysfunction-associated fatty liver disease/nonalcoholic fatty liver disease, and hepatitis B and C contribute to chronic diseases of the liver. Liver fibrosis occurs in all forms of advanced chronic diseases of the liver, the confirmation of which is typically performed by needle biopsy. Imaging approaches for liver diagnosis exist but do not provide sufficient diagnostic accuracy for defining the various stages of fibrosis or steatosis. Therefore, there is a need for improved imaging capabilities to enhance disease diagnosis. Ultrasonography-based photoacoustic imaging has recently emerged as a noninvasive, nonionizing modality, capable of capturing structural details and oxygen saturation changes during disease progression. However, its potential for detecting surrogate metabolic dysfunction-associated fatty liver disease markers, such as collagen and lipids, which are often poorly resolved by other conventional imaging techniques, has yet to be investigated in detail. The novelty of this study lies in the innovative use of spectral photoacoustic imaging for the direct detection and quantification of key biomarkers of liver disease, such as fibrosis, collagen, lipids, and oxygenated and deoxygenated hemoglobin, in a mouse model of steatotic fatty liver disease. Ultrasonography-based photoacoustic imaging, validated with magnetic resonance imaging, effectively identified increases in liver adiposity and fibrosis, enabling the noninvasive detection of changes in liver pathology associated with metabolic dysfunction.
Collapse
Affiliation(s)
- Alissa Keegan
- Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, District of Columbia
| | | | - Yichien Lee
- Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, District of Columbia
| | - Kyle Korolowicz
- Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, District of Columbia
| | - Blythe D Shepard
- Department of Human Science, Georgetown University Medical Center, Washington, District of Columbia
| | - Carolyn M Ecelbarger
- Department of Medicine, Georgetown University Medical Center, Washington, District of Columbia
| | - Mariana Moya Rubiano
- Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, District of Columbia
| | - Maria Laura Avantaggiati
- Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, District of Columbia
| | - Moshe Levi
- Department of Biochemistry and Molecular and Cell Biology and Center for Biological and Biomedical Engineering, Georgetown University Medical Center, Washington, District of Columbia
| | - Laurie Rich
- FUJIFILM VisualSonics Inc., Amsterdam, the Netherlands
| | - Massimo Alfano
- Division of Experimental Oncology/Unit of Urology, Urological Research Institute, Instituto di Ricovero e Cura a Carattere Scientifico Ospedale San Raffaele, Milan, Italy
| | - Avi Rosenberg
- Genitourinary and Autopsy Divisions, Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Stanley Fricke
- Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, District of Columbia; Department of Radiology, Georgetown University Medical Center, Washington, District of Columbia; Center for Translational Imaging, Georgetown University Medical Center, Washington, District of Columbia
| | - Chris Albanese
- Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, District of Columbia; Department of Radiology, Georgetown University Medical Center, Washington, District of Columbia; Center for Translational Imaging, Georgetown University Medical Center, Washington, District of Columbia.
| | - Jithin Jose
- FUJIFILM VisualSonics Inc., Amsterdam, the Netherlands.
| | - Olga Rodriguez
- Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, District of Columbia; Center for Translational Imaging, Georgetown University Medical Center, Washington, District of Columbia
| |
Collapse
|
7
|
Kelly MP, Nikolaev VO, Gobejishvili L, Lugnier C, Hesslinger C, Nickolaus P, Kass DA, Pereira de Vasconcelos W, Fischmeister R, Brocke S, Epstein PM, Piazza GA, Keeton AB, Zhou G, Abdel-Halim M, Abadi AH, Baillie GS, Giembycz MA, Bolger G, Snyder G, Tasken K, Saidu NEB, Schmidt M, Zaccolo M, Schermuly RT, Ke H, Cote RH, Mohammadi Jouabadi S, Roks AJM. Cyclic nucleotide phosphodiesterases as drug targets. Pharmacol Rev 2025; 77:100042. [PMID: 40081105 DOI: 10.1016/j.pharmr.2025.100042] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2024] [Accepted: 01/13/2025] [Indexed: 03/15/2025] Open
Abstract
Cyclic nucleotides are synthesized by adenylyl and/or guanylyl cyclase, and downstream of this synthesis, the cyclic nucleotide phosphodiesterase families (PDEs) specifically hydrolyze cyclic nucleotides. PDEs control cyclic adenosine-3',5'monophosphate (cAMP) and cyclic guanosine-3',5'-monophosphate (cGMP) intracellular levels by mediating their quick return to the basal steady state levels. This often takes place in subcellular nanodomains. Thus, PDEs govern short-term protein phosphorylation, long-term protein expression, and even epigenetic mechanisms by modulating cyclic nucleotide levels. Consequently, their involvement in both health and disease is extensively investigated. PDE inhibition has emerged as a promising clinical intervention method, with ongoing developments aiming to enhance its efficacy and applicability. In this comprehensive review, we extensively look into the intricate landscape of PDEs biochemistry, exploring their diverse roles in various tissues. Furthermore, we outline the underlying mechanisms of PDEs in different pathophysiological conditions. Additionally, we review the application of PDE inhibition in related diseases, shedding light on current advancements and future prospects for clinical intervention. SIGNIFICANCE STATEMENT: Regulating PDEs is a critical checkpoint for numerous (patho)physiological conditions. However, despite the development of several PDE inhibitors aimed at controlling overactivated PDEs, their applicability in clinical settings poses challenges. In this context, our focus is on pharmacodynamics and the structure activity of PDEs, aiming to illustrate how selectivity and efficacy can be optimized. Additionally, this review points to current preclinical and clinical evidence that depicts various optimization efforts and indications.
Collapse
Affiliation(s)
- Michy P Kelly
- Department of Neurobiology, Center for Research on Aging, University of Maryland School of Medicine, Baltimore, Maryland
| | - Viacheslav O Nikolaev
- Institute of Experimental Cardiovascular Research, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Leila Gobejishvili
- Department of Physiology, School of Medicine, University of Louisville, Kentucky, Louisville
| | - Claire Lugnier
- Translational CardioVascular Medicine, CRBS, UR 3074, Strasbourg, France
| | | | - Peter Nickolaus
- Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany
| | - David A Kass
- Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland; Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | | | - Rodolphe Fischmeister
- Université Paris-Saclay, Inserm, Signaling and Cardiovascular Pathophysiology, UMR-S 1180, Orsay, France
| | - Stefan Brocke
- Department of Immunology, UConn Health, Farmington, Connecticut
| | - Paul M Epstein
- Department of Cell Biology, UConn Health, Farmington, Connecticut
| | - Gary A Piazza
- Department of Drug Discovery and Development, Harrison College of Pharmacy, Auburn University, Auburn, Alabama
| | - Adam B Keeton
- Department of Drug Discovery and Development, Harrison College of Pharmacy, Auburn University, Auburn, Alabama
| | - Gang Zhou
- Georgia Cancer Center, Augusta University, Augusta, Georgia
| | - Mohammad Abdel-Halim
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy and Biotechnology, German University in Cairo, Cairo, Egypt
| | - Ashraf H Abadi
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy and Biotechnology, German University in Cairo, Cairo, Egypt
| | - George S Baillie
- School of Cardiovascular and Metabolic Health, University of Glasgow, Glasgow, UK
| | - Mark A Giembycz
- Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
| | | | - Gretchen Snyder
- Molecular Neuropharmacology, Intra-Cellular Therapies Inc (ITI), New York, New York
| | - Kjetil Tasken
- Department of Cancer Immunology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway; Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | - Nathaniel E B Saidu
- Department of Cancer Immunology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway
| | - Martina Schmidt
- Department of Molecular Pharmacology, University of Groningen, Groningen, The Netherlands; Groningen Research Institute for Asthma and COPD, GRIAC, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Manuela Zaccolo
- Department of Physiology, Anatomy and Genetics and National Institute for Health and Care Research Oxford Biomedical Research Centre, University of Oxford, Oxford, United Kingdom
| | - Ralph T Schermuly
- Department of internal Medicine, Justus Liebig University of Giessen, Giessen, Germany
| | - Hengming Ke
- Department of Biochemistry and Biophysics, The University of North Carolina, Chapel Hill, North Carolina
| | - Rick H Cote
- Department of Molecular, Cellular, and Biomedical Sciences, University of New Hampshire, Durham, New Hampshire
| | - Soroush Mohammadi Jouabadi
- Section of Vascular and Metabolic Disease, Department of Internal Medicine, Erasmus MC University Medical Center, Erasmus University Rotterdam, Rotterdam, The Netherlands
| | - Anton J M Roks
- Section of Vascular and Metabolic Disease, Department of Internal Medicine, Erasmus MC University Medical Center, Erasmus University Rotterdam, Rotterdam, The Netherlands.
| |
Collapse
|
8
|
Palomer X, Wang JR, Escalona C, Wu S, Wahli W, Vázquez-Carrera M. Targeting AMPK as a potential treatment for hepatic fibrosis in MASLD. Trends Pharmacol Sci 2025:S0165-6147(25)00065-3. [PMID: 40300935 DOI: 10.1016/j.tips.2025.03.008] [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: 02/20/2025] [Revised: 03/12/2025] [Accepted: 03/27/2025] [Indexed: 05/01/2025]
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common chronic liver disease, and often progresses to hepatic fibrosis, cirrhosis, and liver failure. Despite its increasing prevalence, effective pharmacological treatments for MASLD-related fibrosis remain limited. Recent research has highlighted AMP-activated protein kinase (AMPK) as a key regulator of the processes that promote fibrogenesis, and AMPK activation shows potential in mitigating fibrosis. Advances in AMPK activators and deeper insights into their role in fibrotic pathways have recently revitalized interest in targeting AMPK for fibrosis treatment. This review discusses the molecular mechanisms linking AMPK to hepatic fibrosis and evaluates emerging AMPK-directed therapies. Furthermore, it addresses challenges in clinical translation. Importantly, we combine the latest mechanistic discoveries with recent therapeutic developments to provide a comprehensive perspective on AMPK as a target for hepatic fibrosis treatment.
Collapse
Affiliation(s)
- Xavier Palomer
- Department of Pharmacology, Toxicology, and Therapeutic Chemistry, Faculty of Pharmacy and Food Sciences, University of Barcelona, 08028 Barcelona, Spain; Institute of Biomedicine of the University of Barcelona (IBUB), University of Barcelona, 08028 Barcelona, Spain; Spanish Biomedical Research Center in Diabetes and Associated Metabolic Diseases (CIBERDEM), Instituto de Salud Carlos III, 28029 Madrid, Spain; Pediatric Research Institute, Hospital Sant Joan de Déu, 08950 Esplugues de Llobregat, Barcelona, Spain
| | - Jue-Rui Wang
- Department of Pharmacology, Toxicology, and Therapeutic Chemistry, Faculty of Pharmacy and Food Sciences, University of Barcelona, 08028 Barcelona, Spain; Institute of Biomedicine of the University of Barcelona (IBUB), University of Barcelona, 08028 Barcelona, Spain; Spanish Biomedical Research Center in Diabetes and Associated Metabolic Diseases (CIBERDEM), Instituto de Salud Carlos III, 28029 Madrid, Spain; Pediatric Research Institute, Hospital Sant Joan de Déu, 08950 Esplugues de Llobregat, Barcelona, Spain
| | - Claudia Escalona
- Department of Pharmacology, Toxicology, and Therapeutic Chemistry, Faculty of Pharmacy and Food Sciences, University of Barcelona, 08028 Barcelona, Spain; Institute of Biomedicine of the University of Barcelona (IBUB), University of Barcelona, 08028 Barcelona, Spain; Spanish Biomedical Research Center in Diabetes and Associated Metabolic Diseases (CIBERDEM), Instituto de Salud Carlos III, 28029 Madrid, Spain; Pediatric Research Institute, Hospital Sant Joan de Déu, 08950 Esplugues de Llobregat, Barcelona, Spain
| | - Siyuan Wu
- Department of Pharmacology, Toxicology, and Therapeutic Chemistry, Faculty of Pharmacy and Food Sciences, University of Barcelona, 08028 Barcelona, Spain; Institute of Biomedicine of the University of Barcelona (IBUB), University of Barcelona, 08028 Barcelona, Spain; Spanish Biomedical Research Center in Diabetes and Associated Metabolic Diseases (CIBERDEM), Instituto de Salud Carlos III, 28029 Madrid, Spain; Pediatric Research Institute, Hospital Sant Joan de Déu, 08950 Esplugues de Llobregat, Barcelona, Spain
| | - Walter Wahli
- Center for Integrative Genomics, University of Lausanne, CH-1015 Lausanne, Switzerland; ToxAlim (Research Center in Food Toxicology), Institut National de Recherche pour l'Agriculture, l'Alimentation, et l'Environnement (INRAE), Unité Mixte de Recherche (UMR) 1331, F-31300 Toulouse Cedex, France
| | - Manuel Vázquez-Carrera
- Department of Pharmacology, Toxicology, and Therapeutic Chemistry, Faculty of Pharmacy and Food Sciences, University of Barcelona, 08028 Barcelona, Spain; Institute of Biomedicine of the University of Barcelona (IBUB), University of Barcelona, 08028 Barcelona, Spain; Spanish Biomedical Research Center in Diabetes and Associated Metabolic Diseases (CIBERDEM), Instituto de Salud Carlos III, 28029 Madrid, Spain; Pediatric Research Institute, Hospital Sant Joan de Déu, 08950 Esplugues de Llobregat, Barcelona, Spain.
| |
Collapse
|
9
|
McCary A, Sheu YS, Chesbrough K, Jonas MC. Improved Liver Fibrosis Regression After Direct-Acting Antiviral Therapy in Hepatitis C Patients: A Comparison of Patients With and Without MASLD. Clin Ther 2025:S0149-2918(25)00087-6. [PMID: 40287335 DOI: 10.1016/j.clinthera.2025.03.011] [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: 12/18/2024] [Revised: 03/12/2025] [Accepted: 03/23/2025] [Indexed: 04/29/2025]
Abstract
PURPOSE Chronic Hepatitis C (CHC) often results in liver fibrosis. Therefore, an important benefit of CHC treatment with direct-acting antiviral (DAA) medication is liver fibrosis regression. However, it is unclear how concurrent liver steatosis affects fibrosis regression following DAA therapy. Recent guidelines have defined liver steatosis associated with metabolic syndrome as metabolic dysfunction-associated steatotic liver disease (MASLD). We sought to examine the association of MASLD with the fibrosis regression benefits of DAA treatment for CHC. METHODS We conducted an observational retrospective analysis using electronic health records of patients aged 18-65 who completed DAA therapy for CHC from 2016 through 2022. FIB-4 scores were calculated during three time periods: just prior to DAA initiation, within 6 months post-DAA completion, and within 6-12 months post-DAA completion. These scores categorized liver fibrosis as high risk (>3.25), intermediate risk (1.45-3.25), or low risk (<1.45). An ordinal logistic regression model assessed the degree of fibrosis regression across these periods in CHC patients with and without MASLD. FINDINGS We identified 845 patients with CHC who received DAA therapy, of whom 225 met MASLD criteria. Both CHC patients with and without MASLD exhibited a decrease in FIB-4 category (coefficient = -0.361, P < 0.001) within the year following DAA therapy. The reduction in FIB-4 category post-treatment was more pronounced in the MASLD group compared to the non-MASLD group, as evidenced by a significant interaction between group and time period (coefficient = -0.439, P = 0.004). IMPLICATIONS In our cohort, MASLD was associated with greater liver fibrosis regression in the year following DAA therapy for CHC. This suggests that the concurrent presence of MASLD is not associated with diminished fibrosis regression from DAA therapy. Additional research is needed to determine the exact mechanism responsible for DAA-associated fibrosis regression in patients with MASLD.
Collapse
Affiliation(s)
- Alexis McCary
- Department of Gastroenterology, Mid-Atlantic Permanente Medical Group, Upper Marlboro, Maryland; Mid-Atlantic Permanente Research Institute, Mid-Atlantic Permanente Medical Group, Washington, District of Columbia.
| | - Yi-Shin Sheu
- Mid-Atlantic Permanente Research Institute, Mid-Atlantic Permanente Medical Group, Washington, District of Columbia
| | - Karen Chesbrough
- Mid-Atlantic Permanente Research Institute, Mid-Atlantic Permanente Medical Group, Washington, District of Columbia
| | - M Cabell Jonas
- Mid-Atlantic Permanente Research Institute, Mid-Atlantic Permanente Medical Group, Washington, District of Columbia
| |
Collapse
|
10
|
Lioci G, Gurrado F, Panera N, Bianchi M, De Stefanis C, D’Oria V, Cicolani N, Santini SJ, Schiadà L, Alisi A, Svegliati-Baroni G. Intestinal Activation of LXRα Counteracts Metabolic-Associated Steatohepatitis Features in Mice. Nutrients 2025; 17:1349. [PMID: 40284213 PMCID: PMC12030714 DOI: 10.3390/nu17081349] [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: 03/03/2025] [Revised: 04/09/2025] [Accepted: 04/12/2025] [Indexed: 04/29/2025] Open
Abstract
Background/Objectives: Metabolic dysfunction-associated steatotic liver disease (MASLD) is a growing global health problem and the discovery of drugs is challenging. In this study, we aimed to investigate the effects of intestinal activation of the liver X receptor (LXR)α on MASH. Methods: An intestinal-specific LXRα activation model in mice was established and subjected to MASH development by combining a Western diet and carbon tetrachloride. Lipid metabolism, reverse cholesterol transport (RCT), steatosis, inflammation, and fibrosis were evaluated. In vitro models of steatosis and fibrosis were used to explore the role of scavenger receptor class B type 1 (SRB1). Results: We found that the intestinal activation of LXRα improved several MASLD features, including levels of triglycerides, RCT, steatosis, systemic and hepatic inflammatory profiles, and liver fibrosis. These effects were associated with increased high-density lipoprotein (HDL) levels and hepatic SRB1 expression. In vitro depletion of SRB1 hampered the beneficial effects of HDL on steatosis and fibrogenesis in liver cells by altering the activation of both peroxisome proliferator-activated receptors γ and small mothers against decapentaplegic homolog protein (SMAD)2/3 proteins. Conclusions: Our findings showed that the intestinal activation of LXRα and a parallel induction of hepatic SRB1 are protective against inflammation, steatosis, and advanced liver fibrosis in MASLD.
Collapse
Affiliation(s)
- Gessica Lioci
- Liver Injury and Transplant Unit, Polytechnic University of Marche, 60121 Ancona, Italy; (G.L.); (F.G.); (L.S.); (G.S.-B.)
| | - Fabio Gurrado
- Liver Injury and Transplant Unit, Polytechnic University of Marche, 60121 Ancona, Italy; (G.L.); (F.G.); (L.S.); (G.S.-B.)
| | - Nadia Panera
- Research Unit of Genetics of Complex Phenotypes, Bambino Gesù Children’s Hospital, IRCCS, 00165 Rome, Italy; (N.P.); (M.B.)
| | - Marzia Bianchi
- Research Unit of Genetics of Complex Phenotypes, Bambino Gesù Children’s Hospital, IRCCS, 00165 Rome, Italy; (N.P.); (M.B.)
| | - Cristiano De Stefanis
- Core Facilities, Bambino Gesù Children’s Hospital, IRCCS, 00146 Rome, Italy; (C.D.S.); (V.D.); (N.C.)
| | - Valentina D’Oria
- Core Facilities, Bambino Gesù Children’s Hospital, IRCCS, 00146 Rome, Italy; (C.D.S.); (V.D.); (N.C.)
| | - Nicolò Cicolani
- Core Facilities, Bambino Gesù Children’s Hospital, IRCCS, 00146 Rome, Italy; (C.D.S.); (V.D.); (N.C.)
| | - Silvano Junior Santini
- Department of Life, Health and Environmental Sciences-MESVA, School of Emergency-Urgency Medicine, University of L’Aquila, 67100 L’Aquila, Italy;
| | - Laura Schiadà
- Liver Injury and Transplant Unit, Polytechnic University of Marche, 60121 Ancona, Italy; (G.L.); (F.G.); (L.S.); (G.S.-B.)
| | - Anna Alisi
- Research Unit of Genetics of Complex Phenotypes, Bambino Gesù Children’s Hospital, IRCCS, 00165 Rome, Italy; (N.P.); (M.B.)
| | - Gianluca Svegliati-Baroni
- Liver Injury and Transplant Unit, Polytechnic University of Marche, 60121 Ancona, Italy; (G.L.); (F.G.); (L.S.); (G.S.-B.)
| |
Collapse
|
11
|
Bian C, Luo J, Tang R, Huang H, Zeng Z. The impact of donor liver fibrosis on the outcomes of patients who undergo liver transplant: a cohort study from UNOS database. Front Med (Lausanne) 2025; 12:1547200. [PMID: 40276744 PMCID: PMC12018376 DOI: 10.3389/fmed.2025.1547200] [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: 12/17/2024] [Accepted: 03/11/2025] [Indexed: 04/26/2025] Open
Abstract
Background The increasing prevalence of fibrosis in donor livers raises concerns about its impact on post-transplantation outcomes, though this relationship remains unclear. This study aims to assess the effect of donor liver fibrosis on patient and graft survival following liver transplantation. Methods Data from the UNOS-SRTR registry (1987-2024) were analyzed, focusing on patients who received liver transplants with biopsy-proven fibrosis. The cohort was stratified based on fibrosis grade, and outcomes were compared using Cox regression and Kaplan-Meier survival analysis. Competing risk models were applied to assess specific causes for graft failure, and subgroup analyses explored the sensitivity of fibrosis on transplant outcomes. Results Of the 22,897 patients, 17,926 received non-fibrotic grafts, and 4,971 had grafts with varying fibrosis grades. Donor fibrosis was associated with donor age, steatosis, and portal infiltrate, generally affecting those in better overall condition. Significant differences were observed in patient survival (p = 0.001) and graft survival (p = 0.002) between the fibrosis and non-fibrosis groups. Further analysis revealed that fibrosis increased the risk of malignancy (p = 0.028), cardiovascular disease (p = 0.017), and respiratory failure (p = 0.033), but showed lower rejection rates at six months and one year. Sensitivity analyses confirmed fibrosis as an independent risk factor, with varying effects in subgroups. Conclusion Donor liver fibrosis significantly impacts post-transplant outcomes, notably increasing the risk of all-cause mortality and graft failure. Specific causes of death, such as malignancy and cardiovascular disease, were more prevalent in recipients of fibrotic grafts, highlighting the need for further research to refine donor selection criteria.
Collapse
Affiliation(s)
- Congwen Bian
- Department of Organ Transplantation, The First Affiliated Hospital of Kunming Medical University, Kunming, China
- Department of Surgery, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, Hong Kong SAR, China
| | - Jiajiao Luo
- Department of Organ Transplantation, The First Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Ruizhu Tang
- Department of Clinical Laboratory, The First Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Hanfei Huang
- Department of Organ Transplantation, The First Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Zhong Zeng
- Department of Organ Transplantation, The First Affiliated Hospital of Kunming Medical University, Kunming, China
| |
Collapse
|
12
|
Comi L, Giglione C, Tolaj Klinaku F, Da Dalt L, Ullah H, Daglia M, Magni P. Evaluation of Metabolic Dysfunction-Associated Fatty Liver Disease-Related Pathogenic Mechanisms in Human Steatotic Liver Cell-Based Model: Beneficial Effects of Prunus domestica L. subsp. syriaca Extract. Nutrients 2025; 17:1249. [PMID: 40219006 PMCID: PMC11990314 DOI: 10.3390/nu17071249] [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: 03/03/2025] [Revised: 03/29/2025] [Accepted: 04/01/2025] [Indexed: 04/14/2025] Open
Abstract
Background/Objectives: Disrupted glucose uptake, oxidative stress, and increased de novo lipogenesis are some of the key features of metabolic dysfunction-associated fatty liver disease (MASLD). The modulation of these pathogenic mechanisms using extracts from natural and sustainable sources is a promising strategy to mitigate disease progression. This study aimed to evaluate the effects of Prunus domestica L. subsp. syriaca extract on these processes, taking advantage of a cell-based model of steatotic hepatocytes (HepG2-OA) that recapitulates some key pathophysiological features of MASLD. Methods: The HepG2-OA cell model was generated by treating cells for 7 days with 100 μM oleic acid (OA). The effect of different concentrations (0.01, 0.1, 0.5, and 1 mg/mL) of P. domestica extract was assessed through MTT assay (cell viability), flow cytometry (glucose uptake and reactive oxygen species, ROS, production), spectrophotometry (lipid accumulation), and qRT-PCR (expression of selected genes). Results: P. domestica extract exhibited no cytotoxicity at any tested concentration after 24 and 48 h in the HepG2-OA cells. The extract increased glucose uptake in a dose-dependent fashion after both 6 and 24 h. Additionally, the extract reduced lipid accumulation and downregulated the expression of key lipogenic genes (DGAT1 and FASN). Furthermore, in the HepG2-OA cells, P. domestica extract reduced ROS production and downregulated the expression of oxidative stress-related genes (SOD and CAT). Conclusions: P. domestica extract positively modulated some key molecular mechanisms associated with glucose metabolism, lipogenesis, and oxidative stress, supporting its potential as a nutraceutical candidate for MASLD management.
Collapse
Affiliation(s)
- Laura Comi
- Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, 20133 Milan, Italy; (L.C.); (C.G.); (F.T.K.); (L.D.D.)
| | - Claudia Giglione
- Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, 20133 Milan, Italy; (L.C.); (C.G.); (F.T.K.); (L.D.D.)
| | - Fationa Tolaj Klinaku
- Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, 20133 Milan, Italy; (L.C.); (C.G.); (F.T.K.); (L.D.D.)
| | - Lorenzo Da Dalt
- Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, 20133 Milan, Italy; (L.C.); (C.G.); (F.T.K.); (L.D.D.)
| | - Hammad Ullah
- School of Pharmacy, University of Management and Technology, Lahore 54000, Pakistan;
| | - Maria Daglia
- Department of Pharmacy, University of Naples Federico II, 80168 Naples, Italy;
- International Research Center for Food Nutrition and Safety, Jiangsu University, Zhenjiang 212013, China
| | - Paolo Magni
- Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, 20133 Milan, Italy; (L.C.); (C.G.); (F.T.K.); (L.D.D.)
- IRCCS MultiMedica, 20099 Sesto San Giovanni, Milan, Italy
| |
Collapse
|
13
|
Arvanitakis K, Koufakis T, Cholongitas E, Francque S, Germanidis G. Insights into the results of Resmetirom trials: Can a thyroid hormone receptor agonist be the holy grail of MASH therapy? Pharmacol Ther 2025; 268:108811. [PMID: 39938598 DOI: 10.1016/j.pharmthera.2025.108811] [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: 10/26/2024] [Revised: 01/12/2025] [Accepted: 01/29/2025] [Indexed: 02/14/2025]
Abstract
Despite the heavy individual patient and socioeconomic burden of metabolic dysfunction-associated steatohepatitis (MASH), until recently, no pharmacological therapy for MASH was approved, with available treatment options geared towards associated cardiometabolic risk factors. Accelerated approval of resmetirom, a thyroid hormone receptor-β agonist to be used in conjunction with diet and exercise, marks a significant step forward in the treatment of MASH, offering tempered optimism to healthcare providers and millions of patients around the world for more effective management. Evidence from phase 2 and 3 clinical trials suggests that resmetirom has the potential to alleviate hepatic fibrosis and inflammation and significantly reduce liver lipid content. Notwithstanding this landmark event, the clinical implementation of resmetirom comes with important challenges, for example, ensuring patient access to treatment and demonstrating effects on hard MASH-related outcomes, such as progression to cirrhosis and hepatocellular carcinoma. Additional considerations include the evaluation of co-administration with other hepatoprotective treatments and the assessment of the efficacy in specific MASH sub-phenotypes. Furthermore, the accumulation of real-world data and experience is expected to help answer the remaining questions about the (long-term) effectiveness and safety profile of the drug. The purpose of this article is to provide an updated and critical review of the mechanisms of action, efficacy, and safety of resmetirom based on the latest clinical trials, to define its place within the broader landscape of MASH management, and to highlight current knowledge gaps and opportunities for future research in the field.
Collapse
Affiliation(s)
- Konstantinos Arvanitakis
- Division of Gastroenterology and Hepatology, First Department of Internal Medicine, AHEPA University Hospital, Aristotle University of Thessaloniki, 54636 Thessaloniki, Greece; 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 Propedeutic Department of Internal Medicine, Hippokration General Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Evangelos Cholongitas
- First Department of Internal Medicine, Laiko General Hospital, Medical School of National and Kapodistrian University of Athens, Athens, Greece
| | - Sven Francque
- Department of Gastroenterology and Hepatology, Antwerp University Hospital, Edegem, Belgium; Laboratory of Experimental Medicine and Pediatrics (LEMP), Division of Gastroenterology-Hepatology, Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium
| | - Georgios Germanidis
- Division of Gastroenterology and Hepatology, First Department of Internal Medicine, AHEPA University Hospital, Aristotle University of Thessaloniki, 54636 Thessaloniki, Greece; 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.
| |
Collapse
|
14
|
Gjorgjieva M, Calo N, Sobolewski C, Portius D, Pitetti JL, Berthou F, Ay AS, Peyrou M, Bourgoin L, Maeder C, Fournier M, Correia de Sousa M, Delangre E, Vinet L, Montet X, Sempoux C, Nef S, Foti M. Hepatic IR and IGF1R signaling govern distinct metabolic and carcinogenic processes upon PTEN deficiency in the liver. JHEP Rep 2025; 7:101305. [PMID: 40115165 PMCID: PMC11925173 DOI: 10.1016/j.jhepr.2024.101305] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/14/2024] [Revised: 12/05/2024] [Accepted: 12/10/2024] [Indexed: 03/23/2025] Open
Abstract
Background & Aims Hepatocyte-specific deficiency of the phosphatase and tensin homolog (PTEN) triggers steatosis and the development of hepatic tumors. The hepatoprotective effect of PTEN may partly depend on its ability to block insulin receptor (IR) and insulin-like growth factor 1 receptor (IGF1R) signaling. This study aimed to evaluate the individual/combined contributions of IR and IGF1R to hepatic metabolism and tumorigenesis induced by PTEN deficiency. Methods Mouse models with hepatocyte-specific deletions of Insr, Igf1r, or both, in addition to Pten, were used to investigate the distinct/combined roles of IR and IGF1R. Analyses focused on the impact of these deletions on hepatic steatosis and metabolism, whole-body adiposity, and liver tumor incidence. Results IR and IGF1R signaling contribute to steatosis induced by Pten ablation through distinct mechanisms. Hepatic IGF1R regulates hepatic glucose output and glycogen storage (2.1-fold increase in hepatic glycogen in PTEN-IGF1RKO mice [n = 10], compared with PTENKO mice [n = 7], p <0.0001). In contrast, hepatic IR exerts a stringent regulation on whole-body adiposity (4-fold increase in white adipose tissue volume in PTEN-IRKO mice [n = 5], compared with PTENKO mice [n = 6], p = 0.0004). Interestingly, triple knockout (Insr, Igf1r, and Pten) in hepatocytes of young adult mice is largely asymptomatic, indicating that PTEN deficiency exerts a major overriding control on the effects of Insr and Igf1r deletion. Furthermore, the combined loss of IR and IGF1R signaling in PTEN-deficient livers restrains liver carcinogenesis, but both receptors have individually distinct effects on the malignancy of liver cancers, with IR deficiency reducing overall cancer incidence and IGF1R deficiency promoting malignancy. Conclusions These findings increase our understanding of the intricate interplay between PTEN, IR, and IGF1R signaling and provide valuable insights into potential therapeutic interventions in hepatic disorders and hepatocellular carcinoma. Impact and implications This study underscores the pivotal roles of phosphatase and tensin homolog (PTEN), insulin receptor (IR), and IGF-1 receptor (IGF1R) in controlling liver metabolism, systemic adiposity, and liver cancer progression. Our findings on the distinct and combined effects of these receptors in PTEN-deficient mice offer key insights into the mechanisms driving metabolic dysfunction-associated steatotic liver disease and related hepatocarcinogenesis. In addition, this research reveals the potential of IR and IGF1R as biomarkers in liver cancer development, presenting new opportunities for therapeutic targeting and disease monitoring.
Collapse
Affiliation(s)
- Monika Gjorgjieva
- Department of Cell Physiology and Metabolism, Faculty of Medicine, University of Geneva, Geneva, Switzerland
| | - Nicolas Calo
- Department of Cell Physiology and Metabolism, Faculty of Medicine, University of Geneva, Geneva, Switzerland
| | - Cyril Sobolewski
- Department of Cell Physiology and Metabolism, Faculty of Medicine, University of Geneva, Geneva, Switzerland
| | - Dorothea Portius
- Department of Cell Physiology and Metabolism, Faculty of Medicine, University of Geneva, Geneva, Switzerland
| | - Jean-Luc Pitetti
- Animal Sciences Department, Faculty of Medicine, University of Geneva, CH-1211 Geneva, Switzerland
| | - Flavien Berthou
- Department of Cell Physiology and Metabolism, Faculty of Medicine, University of Geneva, Geneva, Switzerland
| | - Anne-Sophie Ay
- Department of Cell Physiology and Metabolism, Faculty of Medicine, University of Geneva, Geneva, Switzerland
| | - Marion Peyrou
- Department of Cell Physiology and Metabolism, Faculty of Medicine, University of Geneva, Geneva, Switzerland
| | - Lucie Bourgoin
- Department of Cell Physiology and Metabolism, Faculty of Medicine, University of Geneva, Geneva, Switzerland
| | - Christine Maeder
- Department of Cell Physiology and Metabolism, Faculty of Medicine, University of Geneva, Geneva, Switzerland
| | - Margot Fournier
- Department of Cell Physiology and Metabolism, Faculty of Medicine, University of Geneva, Geneva, Switzerland
| | - Marta Correia de Sousa
- Department of Cell Physiology and Metabolism, Faculty of Medicine, University of Geneva, Geneva, Switzerland
| | - Etienne Delangre
- Department of Cell Physiology and Metabolism, Faculty of Medicine, University of Geneva, Geneva, Switzerland
| | - Laurent Vinet
- Department of Radiology, Faculty of Medicine, University of Geneva, Geneva, Switzerland
| | - Xavier Montet
- Department of Radiology, Faculty of Medicine, University of Geneva, Geneva, Switzerland
| | - Christine Sempoux
- Service of Clinical Pathology, Institute of Pathology, Lausanne University Hospital, University of Lausanne, Lausanne, Switzerland
| | - Serge Nef
- Department of Genetic Medicine and Development, Faculty of Medicine, University of Geneva, CH-1211 Geneva, Switzerland
| | - Michelangelo Foti
- Department of Cell Physiology and Metabolism, Faculty of Medicine, University of Geneva, Geneva, Switzerland
| |
Collapse
|
15
|
Narimatsu Y, Kato M, Iwakoshi-Ukena E, Furumitsu M, Ukena K. A murine model of obesity with hyperinsulinemia and hepatic steatosis involving neurosecretory protein GL gene and a low-fat/medium-sucrose diet. Peptides 2025; 186:171376. [PMID: 39993656 DOI: 10.1016/j.peptides.2025.171376] [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: 12/31/2024] [Revised: 02/15/2025] [Accepted: 02/21/2025] [Indexed: 02/26/2025]
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD) featuring hepatic steatosis and insulin dysregulation is becoming a common cause of chronic hepatic diseases. Although the involvement of endocrine disruption in the onset and progression of MASLD is thought to be critical, there are limited effective animal models reflecting hyperinsulinemia and hepatic steatosis. Here, we propose a MASLD mouse model that combines neuropeptide effects and dietary nutrition. We employed chronic overexpression of the gene encoding neurosecretory protein GL (NPGL) in the hypothalamus of ICR mice under a low-fat/medium-sucrose diet (LFMSD). Npgl overexpression promoted fat accumulation in the white adipose tissues in 2 weeks. Basal insulin levels were increased and pancreatic islets expanded following Npgl overexpression. Histological and molecular biological approaches revealed that Npgl overexpression enhanced de novo lipogenesis, leading to hepatic steatosis. Nine-week overexpression of Npgl exacerbated obesity and hyperinsulinemia, resulting in hyperglycemia. Moreover, prolonged Npgl overexpression aggravated fat accumulation in the liver with a change in the lipid metabolic pathway. These findings suggest that Npgl overexpression readily leads to obesity with hyperinsulinemia and hepatic steatosis in ICR mice under an LFMSD.
Collapse
Affiliation(s)
- Yuki Narimatsu
- Laboratory of Neurometabolism, Graduate School of Integrated Sciences for Life, Hiroshima University, Higashi-Hiroshima, Hiroshima 739-8521, Japan.
| | - Masaki Kato
- Laboratory of Neurometabolism, Graduate School of Integrated Sciences for Life, Hiroshima University, Higashi-Hiroshima, Hiroshima 739-8521, Japan
| | - Eiko Iwakoshi-Ukena
- Laboratory of Neurometabolism, Graduate School of Integrated Sciences for Life, Hiroshima University, Higashi-Hiroshima, Hiroshima 739-8521, Japan
| | - Megumi Furumitsu
- Laboratory of Neurometabolism, Graduate School of Integrated Sciences for Life, Hiroshima University, Higashi-Hiroshima, Hiroshima 739-8521, Japan
| | - Kazuyoshi Ukena
- Laboratory of Neurometabolism, Graduate School of Integrated Sciences for Life, Hiroshima University, Higashi-Hiroshima, Hiroshima 739-8521, Japan.
| |
Collapse
|
16
|
Šoša I, Labinac L, Perković M. Metabolic Dysfunction-Associated Steatotic Liver Disease Induced by Microplastics: An Endpoint in the Liver-Eye Axis. Int J Mol Sci 2025; 26:2837. [PMID: 40243419 PMCID: PMC11989125 DOI: 10.3390/ijms26072837] [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: 01/30/2025] [Revised: 03/11/2025] [Accepted: 03/20/2025] [Indexed: 04/18/2025] Open
Abstract
There is a significant, rather than just anecdotal, connection between the liver and the eyes. This connection is evident in noticeable cases such as jaundice, where the sclera has a yellow tint. But this can be seen through even more subtle indicators, such as molecules known as hepatokines. This relationship is not merely anecdotal; in some studies, it is referred to as the "liver-eye axis". Ubiquitous environmental contaminants, such as microplastics (MPs), can enter the bloodstream and human body through the conjunctival sac, nasolacrimal duct, and upper respiratory tract mucosa. Once absorbed, these substances can accumulate in various organs and cause harm. Toxic substances from the surface of the eye can lead to local oxidative damage by inducing apoptosis in corneal and conjunctival cells, and irregularly shaped microparticles can exacerbate this effect. Even other toxicants from the ocular surface may be absorbed into the bloodstream and distributed throughout the body. Environmental toxicology presents a challenge because many pollutants can enter the body through the same ocular route as that used by certain medications. Previous research has indicated that the accumulation of MPs may play a major role in the development of chronic liver disease in humans. It is crucial to investigate whether the buildup of MPs in the liver is a potential cause of fibrosis, or simply a consequence of conditions such as cirrhosis and portal hypertension.
Collapse
Affiliation(s)
- Ivan Šoša
- Department of Anatomy, Faculty of Medicine, University of Rijeka, 51000 Rijeka, Croatia
| | - Loredana Labinac
- Department of Pathology and Cytology, General Hospital Pula, 52100 Pula, Croatia; (L.L.); (M.P.)
| | - Manuela Perković
- Department of Pathology and Cytology, General Hospital Pula, 52100 Pula, Croatia; (L.L.); (M.P.)
| |
Collapse
|
17
|
Wu Q, Yang D, Liu C, Xu T. Alcohol Plus Additional Risk Factors: Rodent Model of Liver Injury. Semin Liver Dis 2025; 45:81-98. [PMID: 39719149 DOI: 10.1055/a-2490-4278] [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] [Indexed: 12/26/2024]
Abstract
Alcohol-associated liver disease (ALD), primarily caused by chronic excessive alcohol consumption, is a leading cause of chronic liver disease worldwide. ALD includes alcohol-associated steatotic liver, alcohol-associated hepatitis (AH), fibrosis, cirrhosis, and can even progress to hepatocellular carcinoma (HCC). Existing research indicates that the risk factors of ALD are quite numerous. In addition to drinking patterns, factors such as aldehyde dehydrogenase 2 (ALDH2) deficiency, smoking, medication administration, high-fat diet (HFD), hepatitis virus infection, and disruption of circadian rhythms can also increase susceptibility to ALD. However, there is limited understanding regarding the exacerbation of liver injury by alcohol plus additional risk factors. This review presents rodent models of EtOH + "X," which simulate the synergistic effects of alcohol and additional risk factors in causing liver injury. These models offer a further exploration of the interactions between alcohol and additional risk factors, advancing the simulation of human ALD and providing a more reliable platform for studying disease mechanisms and exploring therapeutic interventions. We summarize the modeling methods, relevant indicators of liver injury, and focus on the targets of the synergistic effects as well as the associated mechanisms.
Collapse
Affiliation(s)
- Qixiang Wu
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, School of Pharmacy, Anhui Medical University, Hefei, Anhui, P.R. China
- Institute for Liver Diseases of Anhui Medical University, Hefei, Anhui, P.R. China
| | - Dashuai Yang
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, School of Pharmacy, Anhui Medical University, Hefei, Anhui, P.R. China
- Institute for Liver Diseases of Anhui Medical University, Hefei, Anhui, P.R. China
| | - Chixiang Liu
- Department of Blood Transfusion, Southern Medical University, Nanfang Hospital, Guangzhou, P.R. China
- School of Laboratory and Biotechnology, Institute of Antibody Engineering, Southern Medical University, Guangzhou, Guangdong, P.R. China
| | - Tao Xu
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, School of Pharmacy, Anhui Medical University, Hefei, Anhui, P.R. China
- Institute for Liver Diseases of Anhui Medical University, Hefei, Anhui, P.R. China
| |
Collapse
|
18
|
Mo H, Yue P, Li Q, Tan Y, Yan X, Liu X, Xu Y, Luo Y, Palihati S, Yi C, Zhang H, Yuan M, Yang B. The role of liver sinusoidal endothelial cells in metabolic dysfunction-associated steatotic liver diseases and liver cancer: mechanisms and potential therapies. Angiogenesis 2025; 28:14. [PMID: 39899173 DOI: 10.1007/s10456-025-09969-5] [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: 11/25/2024] [Accepted: 01/15/2025] [Indexed: 02/04/2025]
Abstract
Liver sinusoidal endothelial cells (LSECs), with their unique morphology and function, have garnered increasing attention in chronic liver disease research. This review summarizes the critical roles of LSECs under physiological conditions and in two representative chronic liver diseases: metabolic dysfunction-associated steatotic liver disease (MASLD) and liver cancer. Under physiological conditions, LSECs act as selective barriers, regulating substance exchange and hepatic blood flow. Interestingly, LSECs exhibit contrasting roles at different stages of disease progression: in the early stages, they actively resist disease advancement and help restore sinusoidal homeostasis; whereas in later stages, they contribute to disease worsening. During this transition, LSECs undergo capillarization, lose their characteristic markers, and become dysfunctional. As the disease progresses, LSECs closely interact with hepatocytes, hepatic stellate cells, various immune cells, and tumor cells, driving processes such as steatosis, inflammation, fibrosis, angiogenesis, and carcinogenesis. Consequently, targeting LSECs represents a promising therapeutic strategy for chronic liver diseases. Relevant therapeutic targets and potential drugs are summarized in this review.
Collapse
Affiliation(s)
- Hanjun Mo
- Abdominal Oncology Ward, Division of Medical Oncology, Cancer Center, West China Hospital, Sichuan University, No. 37 Guoxue Alley, Chengdu, 610041, Sichuan, China
| | - Pengfei Yue
- Abdominal Oncology Ward, Division of Medical Oncology, Cancer Center, West China Hospital, Sichuan University, No. 37 Guoxue Alley, Chengdu, 610041, Sichuan, China
| | - Qiaoqi Li
- Abdominal Oncology Ward, Division of Medical Oncology, Cancer Center, West China Hospital, Sichuan University, No. 37 Guoxue Alley, Chengdu, 610041, Sichuan, China
| | - Yinxi Tan
- Department of Nutrition and Food Hygiene, School of Public Health, Peking University, Beijing, China
| | - Xinran Yan
- Department of Nutrition, School of Public Health, Zhejiang University School of Medicine, Hangzhou, China
| | - Xinyue Liu
- Department of Nutrition and Food Hygiene, West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu, China
| | - Yuanwei Xu
- Department of Cardiology, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Yingzhe Luo
- Department of Medical Oncology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu University of Traditional Chinese Medicine, No. 39 Shierqiao Road, Chengdu, 610075, Sichuan, China
| | - Suruiya Palihati
- Abdominal Oncology Ward, Division of Medical Oncology, Cancer Center, West China Hospital, Sichuan University, No. 37 Guoxue Alley, Chengdu, 610041, Sichuan, China
| | - Cheng Yi
- Abdominal Oncology Ward, Division of Medical Oncology, Cancer Center, West China Hospital, Sichuan University, No. 37 Guoxue Alley, Chengdu, 610041, Sichuan, China.
| | - Hua Zhang
- Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE, West China Second University Hospital, Sichuan University, No. 20, Section 3, South Renmin Road, Chengdu, 610041, China.
- Key Laboratory of Chronobiology (Sichuan University), National Health Commission of China, Chengdu, 610041, China.
| | - Minlan Yuan
- Mental Health Center and Psychiatric Laboratory, The State Key Laboratory of Biotherapy, West China Hospital of Sichuan University, No. 37 Guoxue Alley, Chengdu, 610041, China.
| | - Biao Yang
- Abdominal Oncology Ward, Division of Medical Oncology, Cancer Center, West China Hospital, Sichuan University, No. 37 Guoxue Alley, Chengdu, 610041, Sichuan, China.
| |
Collapse
|
19
|
Gou GE, Li T, Liu CR, Meng T, Li YP. Potential mechanisms and therapeutic prospects of the association between Helicobacter pylori infection and metabolic dysfunction-associated steatohepatitis. World J Hepatol 2025; 17:101798. [PMID: 39871896 PMCID: PMC11736473 DOI: 10.4254/wjh.v17.i1.101798] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/27/2024] [Revised: 11/13/2024] [Accepted: 11/22/2024] [Indexed: 01/06/2025] Open
Abstract
Helicobacter pylori (H. pylori) infection is a known inducer of various gastrointestinal diseases, including gastritis, gastric ulcers, and gastric cancer. However, in recent years, research on the potential association between H. pylori infection and metabolic dysfunction-associated steatohepatitis (MASH) has been scarce. This large-scale multicenter study, covering more than 360 hospitals across 26 medical systems in the United States, systematically evaluated the association between H. pylori infection and MASH. This paper reviews the innovative aspects of this study, discusses its significance in the current research field of H. pylori and liver diseases, analyzes potential molecular mechanisms, and suggests future research directions and therapeutic prospects.
Collapse
Affiliation(s)
- Guo-E Gou
- Department of Infectious Diseases, Xi'an Jiaotong University Second Affiliated Hospital, Xi'an 710004, Shaanxi Province, China
| | - Ting Li
- Department of Infectious Diseases, Xi'an Jiaotong University Second Affiliated Hospital, Xi'an 710004, Shaanxi Province, China
| | - Chen-Rui Liu
- Department of Infectious Diseases, Xi'an Jiaotong University Second Affiliated Hospital, Xi'an 710004, Shaanxi Province, China
| | - Ting Meng
- Department of Infectious Diseases, Xi'an Jiaotong University Second Affiliated Hospital, Xi'an 710004, Shaanxi Province, China
| | - Ya-Ping Li
- Department of Infectious Diseases, Xi'an Jiaotong University Second Affiliated Hospital, Xi'an 710004, Shaanxi Province, China.
| |
Collapse
|
20
|
Xin X, Ni Y, Wang J, Wu F, Liu M, Wu L, Dai J, Wu C, Song X, Zhang W, Yang G, Shen R, Zhu X. Single-Cell RNA Sequencing Reveals Macrophage Dynamics During MASH in Leptin-Deficient Rats. Cells 2025; 14:96. [PMID: 39851524 PMCID: PMC11763963 DOI: 10.3390/cells14020096] [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: 11/06/2024] [Revised: 01/06/2025] [Accepted: 01/07/2025] [Indexed: 01/26/2025] Open
Abstract
Macrophages play important roles in metabolic dysfunction-associated steatohepatitis (MASH), an advanced and inflammatory stage of metabolic dysfunction-associated steatotic liver disease (MASLD). In humans and mice, the cellular heterogeneity and diverse function of hepatic macrophages in MASH have been investigated by single cell RNA sequencing (scRNA-seq). However, little is known about their roles in rats. Here, we collected liver tissues at the postnatal week 16, when our previously characterized Lep∆I14/∆I14 rats developed MASH phenotypes. By scRNA-seq, we found an increase in the number of macrophages and endothelial cells and a decrease in that of NK and B cells. Hepatic macrophages in rats underwent a unique M1 to M2 transition without expression of the classical markers such as Arg1 and Nos2, except for Cd163. Lipid-associated macrophages (LAMs) were increased, which could be detected by the antibody against Cd63. In the microenvironment, macrophages had an increased number of interactions with hepatocytes, myofibroblasts, T cells, neutrophils, and dendritic cells, while their interaction strengths remained unchanged. Finally, the macrophage migration inhibitory factor (MIF) pathway was identified as the top upregulated cell-communication pathway in MASH. In conclusion, we dissected hepatic macrophage dynamics during MASH at single cell resolution and provided fundamental tools for the investigation of MASH in rat models.
Collapse
Affiliation(s)
- Xiaoming Xin
- School of Pharmacy, Shanghai University of Medicine and Health Sciences, Shanghai 201318, China; (X.X.); (Y.N.); (J.W.); (M.L.); (L.W.); (J.D.); (C.W.); (X.S.)
| | - Yaohua Ni
- School of Pharmacy, Shanghai University of Medicine and Health Sciences, Shanghai 201318, China; (X.X.); (Y.N.); (J.W.); (M.L.); (L.W.); (J.D.); (C.W.); (X.S.)
| | - Jing Wang
- School of Pharmacy, Shanghai University of Medicine and Health Sciences, Shanghai 201318, China; (X.X.); (Y.N.); (J.W.); (M.L.); (L.W.); (J.D.); (C.W.); (X.S.)
| | - Fenglin Wu
- School of Clinical Medicine, Shanghai University of Medicine and Health Sciences, Shanghai 201318, China; (F.W.); (G.Y.)
| | - Meichen Liu
- School of Pharmacy, Shanghai University of Medicine and Health Sciences, Shanghai 201318, China; (X.X.); (Y.N.); (J.W.); (M.L.); (L.W.); (J.D.); (C.W.); (X.S.)
| | - Lingjuan Wu
- School of Pharmacy, Shanghai University of Medicine and Health Sciences, Shanghai 201318, China; (X.X.); (Y.N.); (J.W.); (M.L.); (L.W.); (J.D.); (C.W.); (X.S.)
| | - Jiaxing Dai
- School of Pharmacy, Shanghai University of Medicine and Health Sciences, Shanghai 201318, China; (X.X.); (Y.N.); (J.W.); (M.L.); (L.W.); (J.D.); (C.W.); (X.S.)
| | - Chenglin Wu
- School of Pharmacy, Shanghai University of Medicine and Health Sciences, Shanghai 201318, China; (X.X.); (Y.N.); (J.W.); (M.L.); (L.W.); (J.D.); (C.W.); (X.S.)
| | - Xiaolei Song
- School of Pharmacy, Shanghai University of Medicine and Health Sciences, Shanghai 201318, China; (X.X.); (Y.N.); (J.W.); (M.L.); (L.W.); (J.D.); (C.W.); (X.S.)
| | - Wang Zhang
- Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, Shanghai 201210, China;
| | - Guangrui Yang
- School of Clinical Medicine, Shanghai University of Medicine and Health Sciences, Shanghai 201318, China; (F.W.); (G.Y.)
| | - Ruling Shen
- Shanghai Academy of Sciences & Technology Institute of Model Animals Transformation, Shanghai Laboratory Animal Research Center, Shanghai 201203, China
| | - Xianmin Zhu
- Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, Shanghai 201210, China;
- Shanghai Academy of Sciences & Technology Institute of Model Animals Transformation, Shanghai Laboratory Animal Research Center, Shanghai 201203, China
| |
Collapse
|
21
|
Hellen DJ, Ungerleider J, Tevonian E, Sphabmixay P, Roy P, Lewis C, Jeppesen J, Demozay D, Griffith LG. A Microphysiological Model of Progressive Human Hepatic Insulin Resistance. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2025.01.08.631261. [PMID: 39829839 PMCID: PMC11741310 DOI: 10.1101/2025.01.08.631261] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 01/22/2025]
Abstract
Background & Aims Hepatic insulin resistance is a fundamental phenomenon observed in both Type 2 diabetes (T2D) and metabolic (dysfunction) associated fatty liver disease (MAFLD). The relative contributions of nutrients, hyperinsulinemia, hormones, inflammation, and other cues are difficult to parse in vivo as they are convoluted by interplay between the local and systemic events. Here, we used a well-established human liver microphysiological system (MPS) to establish a physiologically-relevant insulin-responsive metabolic baseline and probe how primary human hepatocytes respond to controlled perturbations in insulin, glucose, and free fatty acids (FFAs). Methods Replicate liver MPS were maintained in media with either 200 pM (normal) or 800 pM (T2D) insulin for up to 3 weeks. Conditions of standard glucose (5.5 mM), hyperglycemia (11 mM glucose), normal (20μM) and elevated FFA (100 μM), alone and in combination were used at each insulin concentration, either continuously or reversing back to standard media after 2 weeks of simulated T2D conditions. Hepatic glucose production, activation of signaling pathways, insulin clearance, transcriptome analysis, and intracellular lipid and bile acid accumulation were assessed. Results Hyperinsulinemia alone induces insulin resistance after one week of exposure, while hyperglycemia and increased FFAs significantly exacerbate this phenotype. Hyperinsulinemia, along with elevated glucose and FFAs, transcriptionally predisposes hepatocytes to insulin resistance through altered metabolic and immune signaling pathways. The phenotypes observed in hyperinsulinemia and nutrient overload are partially reversible upon return to normophysiologic conditions. Conclusions Our enhanced in vitro model, replicating multiple aspects of the insulin-resistant condition, offers improved insights into disease mechanisms with relevance to human physiology.
Collapse
Affiliation(s)
- Dominick J. Hellen
- Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, 02139 US
| | - Jessica Ungerleider
- Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, 02139 US
| | - Erin Tevonian
- Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, 02139 US
| | - Pierre Sphabmixay
- Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, 02139 US
| | - Priyatanu Roy
- Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, 02139 US
| | - Caroline Lewis
- Whitehead Institute for Biomedical Research, Cambridge, MA, 02139 US
| | - Jacob Jeppesen
- Whitehead Institute for Biomedical Research, Cambridge, MA, 02139 US
- Liver Disease, Novo Nordisk A/S, Måløv, Denmark
| | | | - Linda G. Griffith
- Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, 02139 US
| |
Collapse
|
22
|
Longo L, Guerreiro GTS, Behrens L, Pereira MHM, Pinzon CE, Cerski CTS, Uribe-Cruz C, Álvares-da-Silva MR. Rifaximin prophylaxis in MASLD‑hepatocellular carcinoma: Lessons from a negative animal model. Biomed Rep 2025; 22:4. [PMID: 39529613 PMCID: PMC11552077 DOI: 10.3892/br.2024.1882] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2024] [Accepted: 08/13/2024] [Indexed: 11/16/2024] Open
Abstract
The incidence of hepatocellular carcinoma (HCC) has been rising, particularly among individuals diagnosed with metabolic dysfunction-associated steatotic liver disease. In the present study, the prophylactic effects of rifaximin (RIF) on HCC, inflammatory markers and cardiovascular risk (CVR) were investigated in an animal model. Adult Sprague-Dawley rats were randomly allocated into three groups (n=10, each): Control [standard diet/water plus gavage with vehicle (Veh)], HCC [high-fat choline deficient diet (HFCD)/diethylnitrosamine (DEN) in drinking water/Veh gavage] and RIF [HFCD/DEN/RIF (50 mg/kg/day) gavage] groups. After euthanasia at week 16, biochemical/inflammatory markers and the liver histology were assessed. The results demonstrated that the HCC and RIF animals had a significant increase in fresh liver weight, liver weight/body weight ratio, serum total cholesterol (TC), high-density lipoprotein-cholesterol, triglycerides, hepatic lipid accumulation and hepatic concentration of triglycerides and TC, relative to the controls (P<0.001, for all). Additionally, the HCC and RIF animals had higher plasminogen activator inhibitor, intercellular adhesion molecule-1, E-selectin and CVR scores than the controls (P<0.001, for all). The HCC animals had higher interleukin (IL)-1β (P=0.011), IL-10 (P<0.001), toll-like receptor-2 (P=0.012), lipopolysaccharide-binding protein (P=0.018) and metalloproteinase-2 (P=0.003) levels than the RIF animals. Furthermore, liver steatosis, inflammation and fibrosis, along with increased collagen fiber deposition occurred in the HCC and RIF groups. However, HCC occurred only in 2 RIF rats. In conclusion, although most animals did not develop HCC in the present study, RIF positively affected liver inflammation markers involved in steatohepatitis pathogenesis.
Collapse
Affiliation(s)
- Larisse Longo
- Graduate Program in Gastroenterology and Hepatology, Federal University of Rio Grande do Sul, Porto Alegre, Rio Grande do Sul 90035-003, Brazil
- Experimental Laboratory of Hepatology and Gastroenterology, Center for Experimental Research, Hospital de Clínicas de Porto Alegre, Porto Alegre, Rio Grande do Sul 90035-903, Brazil
| | - Gabriel Tayguara Silveira Guerreiro
- Graduate Program in Gastroenterology and Hepatology, Federal University of Rio Grande do Sul, Porto Alegre, Rio Grande do Sul 90035-003, Brazil
- Experimental Laboratory of Hepatology and Gastroenterology, Center for Experimental Research, Hospital de Clínicas de Porto Alegre, Porto Alegre, Rio Grande do Sul 90035-903, Brazil
| | - Luiza Behrens
- Experimental Laboratory of Hepatology and Gastroenterology, Center for Experimental Research, Hospital de Clínicas de Porto Alegre, Porto Alegre, Rio Grande do Sul 90035-903, Brazil
| | - Matheus Henrique Mariano Pereira
- Experimental Laboratory of Hepatology and Gastroenterology, Center for Experimental Research, Hospital de Clínicas de Porto Alegre, Porto Alegre, Rio Grande do Sul 90035-903, Brazil
| | - Carlos Eduardo Pinzon
- Experimental Laboratory of Hepatology and Gastroenterology, Center for Experimental Research, Hospital de Clínicas de Porto Alegre, Porto Alegre, Rio Grande do Sul 90035-903, Brazil
| | - Carlos Thadeu Schmidt Cerski
- Graduate Program in Gastroenterology and Hepatology, Federal University of Rio Grande do Sul, Porto Alegre, Rio Grande do Sul 90035-003, Brazil
- Unit of Surgical Pathology, Hospital de Clínicas de Porto Alegre, Porto Alegre, Rio Grande do Sul 90035-903, Brazil
| | - Carolina Uribe-Cruz
- Graduate Program in Gastroenterology and Hepatology, Federal University of Rio Grande do Sul, Porto Alegre, Rio Grande do Sul 90035-003, Brazil
- Experimental Laboratory of Hepatology and Gastroenterology, Center for Experimental Research, Hospital de Clínicas de Porto Alegre, Porto Alegre, Rio Grande do Sul 90035-903, Brazil
- Faculty of Health Sciences, Catholic University of The Missions, Posadas, Misiones 3300, Argentina
| | - Mário Reis Álvares-da-Silva
- Graduate Program in Gastroenterology and Hepatology, Federal University of Rio Grande do Sul, Porto Alegre, Rio Grande do Sul 90035-003, Brazil
- Experimental Laboratory of Hepatology and Gastroenterology, Center for Experimental Research, Hospital de Clínicas de Porto Alegre, Porto Alegre, Rio Grande do Sul 90035-903, Brazil
- Division of Gastroenterology, Hospital de Clínicas de Porto Alegre, Porto Alegre, Rio Grande do Sul 90035-903, Brazil
- National Council for Scientific and Technological Development Researcher, Brasília 71.605-001, Brazil
| |
Collapse
|
23
|
Charoensuk L, Thongpon P, Sitthirach C, Chaidee A, Intuyod K, Pairojkul C, Khin EHH, Jantawong C, Thumanu K, Pinlaor P, Hongsrichan N, Pinlaor S. High-fat/high-fructose diet and Opisthorchis viverrini infection promote metabolic dysfunction-associated steatotic liver disease via inflammation, fibrogenesis, and metabolic dysfunction. Acta Trop 2025; 261:107491. [PMID: 39643028 DOI: 10.1016/j.actatropica.2024.107491] [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: 10/03/2024] [Revised: 11/13/2024] [Accepted: 12/02/2024] [Indexed: 12/09/2024]
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD) and opisthorchiasis, caused by Opisthorchis viverrini (O. viverrini) infection, frequently co-exist in Northeast Thailand. However, the underlying pathophysiology remains unknown. We aimed to investigate the effect of a high-fat/high-fructose (HFF) diet combined with O. viverrini infection on MASLD. Four groups each of ten male golden hamsters were established: normal controls (NC), O. viverrini-infected (OV), HFF-fed, and HFF-fed plus O. viverrini infection (HFF+OV). After four months of treatment, histopathological study indicated substantial hepatic damage in groups given the HFF diet. In particular, the HFF+OV group demonstrated marked lipid-droplet accumulation, hepatocyte ballooning, inflammatory-cell clustering, and widespread fibrosis. Biochemical tests indicated that the HFF+OV group had the highest concentrations of alanine aminotransferase and triglycerides, but cholesterol and low-density lipoprotein levels had increased in both HFF groups. Increased expression of Tgf-β1 and α-SMA, indicative of greater fibrosis, was demonstrated by picrosirius-red staining in the HFF+OV group. There was a significant increase in levels of inflammatory markers (HMGB-1, p65, and F4/80) and expression of genes related to the synthesis of fatty acids and glucose. FTIR microspectroscopy revealed distinct changes in fatty acids and proteins, associated with the more pronounced histopathology and impaired liver function in the HFF+OV group. The findings indicate that the interplay of a HFF diet and O. viverrini infection aggravates the progression of MASLD by augmenting liver damage, inflammation, fibrogenesis, and metabolic dysfunction. This study highlights the significance of incorporating both nutritional and infection factors into the management of liver disorders, especially in areas where opisthorchiasis is common.
Collapse
Affiliation(s)
- Lakhanawan Charoensuk
- Department of Clinical Pathology, Faculty of Medicine Vajira Hospital, Navamindradhiraj University, Bangkok 10300, Thailand; Cholangiocarcinoma Research Institute, Khon Kaen University, Thailand
| | - Phonpilas Thongpon
- Department of Parasitology, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand; Cholangiocarcinoma Research Institute, Khon Kaen University, Thailand
| | - Chutima Sitthirach
- Department of Parasitology, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand; Cholangiocarcinoma Research Institute, Khon Kaen University, Thailand
| | - Apisit Chaidee
- Department of Parasitology, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand; Cholangiocarcinoma Research Institute, Khon Kaen University, Thailand
| | - Kitti Intuyod
- Department of Pathology, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand; Cholangiocarcinoma Research Institute, Khon Kaen University, Thailand
| | - Chawalit Pairojkul
- Department of Pathology, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand; Cholangiocarcinoma Research Institute, Khon Kaen University, Thailand
| | - Ei Htet Htet Khin
- Department of Parasitology, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand; Cholangiocarcinoma Research Institute, Khon Kaen University, Thailand
| | - Chanakan Jantawong
- Department of Medical Technology, Faculty of Allied Health Science, Nakhonratchasima College, Nakhon Ratchasima 30000, Thailand; Cholangiocarcinoma Research Institute, Khon Kaen University, Thailand
| | - Kanjana Thumanu
- Synchrotron Light Research Institute (Public Organization), Nakhon Ratchasima 30000, Thailand
| | - Porntip Pinlaor
- Centre for Research and Development of Medical Diagnostic Laboratories, Faculty of Associated Medical Sciences, Khon Kaen University, Khon Kaen 40002, Thailand; Cholangiocarcinoma Research Institute, Khon Kaen University, Thailand
| | - Nuttanan Hongsrichan
- Department of Parasitology, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand; Cholangiocarcinoma Research Institute, Khon Kaen University, Thailand
| | - Somchai Pinlaor
- Department of Parasitology, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand; Cholangiocarcinoma Research Institute, Khon Kaen University, Thailand.
| |
Collapse
|
24
|
Gilgenkrantz H, Sayegh RA, Lotersztajn S. Immunoregulation of Liver Fibrosis: New Opportunities for Antifibrotic Therapy. Annu Rev Pharmacol Toxicol 2025; 65:281-299. [PMID: 39259981 DOI: 10.1146/annurev-pharmtox-020524-012013] [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] [Indexed: 09/13/2024]
Abstract
Liver fibrosis develops in response to chronic liver injury and is characterized by a sustained inflammatory response that leads to excessive collagen deposition by myofibroblasts. The fibrogenic response is governed by the release of inflammatory mediators from innate, adaptive, and innate-like lymphoid cells and from nonprofessional immune cells (i.e., epithelial cells, hepatic myofibroblasts, and liver sinusoidal endothelial cells). Upon removal of the underlying cause, liver fibrosis can resolve via activation of specific immune cell subsets. Despite major advances in the understanding of fibrosis pathogenesis, there is still no approved antifibrotic therapy. This review summarizes our current knowledge of the immune cell landscape and the inflammatory mechanisms underlying liver fibrosis progression and regression. We discuss how reprogramming immune cell phenotype, in particular through targeting selective inflammatory pathways or modulating cell-intrinsic metabolism, may be translated into antifibrogenic therapies.
Collapse
Affiliation(s)
- Helene Gilgenkrantz
- Université Paris Cité, INSERM, UMR-S1149, Centre de Recherche sur l'Inflammation (CRI), Paris, France;
| | - Rola Al Sayegh
- Université Paris Cité, INSERM, UMR-S1149, Centre de Recherche sur l'Inflammation (CRI), Paris, France;
| | - Sophie Lotersztajn
- Université Paris Cité, INSERM, UMR-S1149, Centre de Recherche sur l'Inflammation (CRI), Paris, France;
| |
Collapse
|
25
|
Joshi V, Carter D, Chen AE, Murphy K, Higgins JW, Gurel M, Chilin Fuentes D, Rosenthal SB, Fisch KM, Kisseleva T, Brenner DA. Induction of MASH in three-dimensional bioprinted human liver tissue. PLoS One 2024; 19:e0312615. [PMID: 39775546 PMCID: PMC11684678 DOI: 10.1371/journal.pone.0312615] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2024] [Accepted: 10/09/2024] [Indexed: 01/11/2025] Open
Abstract
Metabolic dysfunction-associated steatohepatitis (MASH), formerly known as nonalcoholic steatohepatitis (MASH), is a major risk factor for cirrhosis and hepatocellular carcinoma (HCC) and a leading cause of liver transplantation. MASH is caused by an accumulation of toxic fat molecules in the hepatocyte which leads to inflammation and fibrosis. Inadequate human "MASH in a dish" models have limited our advances in understanding MASH pathogenesis and in drug discovery. This study uses complex multicellular 3D bioprinting, combining hepatocytes with nonparenchymal cells in physiologically relevant cell ratios using biocompatible hydrogels to generate bioinks Bioprinted human liver tissues consisting of the four major cell types, (hepatocytes, liver endothelial cells, Kupffer cells, and hepatic stellate cells) are generated from cells purified from normal human livers, using this complex bioprinting platform. These liver tissues are incubated in a cocktail consisting of fatty acids, lipopolysaccharide (LPS), and fructose to produce a MASH phenotype in comparison to liver tissues incubated in control media. Furthermore, these bioprinted liver tissues are of sufficient size to undergo histological processing and immunohistchemistry comparable to classic clinical pathological analysis. The MASH liver tissues develop hepatocyte steatosis, inflammation, and fibrosis, in response to the MASH induction media. Additionally, the transcriptome of the MASH tissues differed significantly from the healthy tissues and more closely resembled the transcriptome of biopsies of MASH livers from patients Thus, this study has developed a MASH bioprinted liver tissue suitable for studies on pathophysiology and drug discovery.
Collapse
Affiliation(s)
- Vaidehi Joshi
- Organovo, Inc., San Diego, California, United States of America
| | - Dwayne Carter
- Organovo, Inc., San Diego, California, United States of America
| | - Alice E. Chen
- Organovo, Inc., San Diego, California, United States of America
| | - Keith Murphy
- Organovo, Inc., San Diego, California, United States of America
| | | | - Mediha Gurel
- Organovo, Inc., San Diego, California, United States of America
| | - Daisy Chilin Fuentes
- University of California, San Diego, La Jolla, California, United States of America
| | - Sara Brin Rosenthal
- University of California, San Diego, La Jolla, California, United States of America
| | - Kathleen M. Fisch
- University of California, San Diego, La Jolla, California, United States of America
| | - Tatiana Kisseleva
- University of California, San Diego, La Jolla, California, United States of America
| | - David A. Brenner
- University of California, San Diego, La Jolla, California, United States of America
- Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California, United States of America
| |
Collapse
|
26
|
Zou X, Brigstock D. Extracellular Vesicles from Mesenchymal Stem Cells: Potential as Therapeutics in Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD). Biomedicines 2024; 12:2848. [PMID: 39767754 PMCID: PMC11673942 DOI: 10.3390/biomedicines12122848] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2024] [Revised: 12/06/2024] [Accepted: 12/12/2024] [Indexed: 01/03/2025] Open
Abstract
Background/Objectives: Metabolic dysfunction-associated steatotic liver disease (MASLD) is characterized by the accumulation of triglycerides within hepatocytes, which can progress to more severe conditions, such as metabolic dysfunction-associated steatohepatitis (MASH), which may include progressive fibrosis, leading to cirrhosis, cancer, and death. This goal of this review is to highlight recent research showing the potential of mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) in reducing the key pathogenic pathways of MASLD or MASH. Methods: Relevant published studies were identified using PubMed with one or more of the following search terms: MASLD, MASH, NAFLD, NASH, exosome, extracellular vesicle (EV), therapy, and/or mesenchymal stem cells (MSC). The primary literature were subsequently downloaded and summarized. Results: Using in vitro or in vivo models, MSC-EVs have been found to counteract oxidative stress, a significant contributor to liver injury in MASH, and to suppress disease progression, including steatosis, inflammation, and, in a few instances, fibrosis. Some of these outcomes have been attributed to specific EV cargo components including microRNAs and proteins. Thus, MSC-EVs enriched with these types of molecules may have improved the therapeutic efficacy for MASLD/MASH and represent a novel approach to potentially halt or reverse the disease process. Conclusions: MSC-EVs are attractive therapeutic agents for treating MASLD/MASH. Further studies are necessary to validate the clinical applicability and efficacy of MSC-EVs in human MASH patients, focusing on optimizing delivery strategies and identifying the pathogenic pathways that are targeted by specific EV components.
Collapse
Affiliation(s)
- Xue Zou
- Center for Clinical and Translational Research, The Abigail Wexner Research Institute at Nationwide Children’s Hospital, Columbus, OH 43205, USA;
| | - David Brigstock
- Center for Clinical and Translational Research, The Abigail Wexner Research Institute at Nationwide Children’s Hospital, Columbus, OH 43205, USA;
- Department of Surgery, Wexner Medical Center, The Ohio State University, Columbus, OH 43212, USA
| |
Collapse
|
27
|
Au K, Zheng MH, Lee WJ, Ghanem OM, Mahawar K, Shabbir A, le Roux CW, Targher G, Byrne CD, Yilmaz Y, Valenti L, Sebastiani G, Treeprasertsuk S, Hui HX, Sakran N, Neto MG, Kermansaravi M, Kow L, Seki Y, Tham KW, Dang J, Cohen RV, Stier C, AlSabah S, Oviedo RJ, Chiappetta S, Parmar C, Yang W. Resmetirom and Metabolic Dysfunction-Associated Steatohepatitis: Perspectives on Multidisciplinary Management from Global Healthcare Professionals. Curr Obes Rep 2024; 13:818-830. [PMID: 39110384 DOI: 10.1007/s13679-024-00582-z] [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] [Accepted: 07/25/2024] [Indexed: 08/25/2024]
Abstract
PURPOSE OF REVIEW The approval of resmetirom brings great hope to patients with metabolic dysfunction-associated steatohepatitis (MASH). The purpose of this review is to explore its impact on the global health environment. The implementation of multidisciplinary management MASH is proposed. RECENT FINDINGS Resmetirom has benefits in the treatment of MASH, and its safety and effectiveness have been studied. The adverse events (AEs) need to be noticed. To improve patient outcomes, a multimodal approach with medication such as resmetirom, combined with metabolic and bariatric surgery (MBS) and lifestyle interventions can be conducted. MASH, a liver disease linked with obesity, is a challenging global healthcare burden compounded by the absence of any approved pharmacotherapy. The recent conditional approval by the Food and Drug Administration (FDA) in the United States of resmetirom, an oral, liver-directed, thyroid hormone receptor beta-selective agonist, marks a significant milestone, offering a treatment option for adults with non-cirrhotic MASH and who have moderate to advanced liver fibrosis. This narrative review discusses the efficacy and safety of resmetirom and its role in the therapeutic landscape of MASH treatment. Despite the promising hepatoprotective effect of resmetirom on histological liver endpoints, its use need further research, particularly regarding ethnic differences, effectiveness and cost-effectiveness, production scalability, social acceptance and accessibility. In addition, integrating resmetirom with other multidisciplinary therapeutic approaches, including lifestyle changes and MBS, might further improve clinical liver-related and cardiometabolic outcomes of individuals with MASH. This review highlights the importance of a comprehensive treatment strategy, supporting continued innovation and collaborative research to refine treatment guidelines and consensus for managing MASH, thereby improving clinical patient outcomes in the growing global epidemic of MASH. Studies done to date have been relatively short and ongoing, the course of the disease is highly variable, the conditions of various patients vary, and given this complex clinical phenotype, it may take many years of clinical trials to show long-term benefits.
Collapse
Affiliation(s)
- Kahei Au
- Department of Metabolic and Bariatric Surgery, The First Affiliated Hospital of Jinan University, No. 613 Huangpu Avenue West, Guangzhou, China
| | - Ming-Hua Zheng
- Department of Hepatology, MAFLD Research Center, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
- Key Laboratory of Diagnosis and Treatment for The Development of Chronic Liver Disease in Zhejiang Province, Wenzhou, China
| | - Wei-Jei Lee
- Medical Weight Loss Center, China Medical University Shinchu Hospital, Zhubei City, Taiwan
| | - Omar M Ghanem
- Department of Surgery, Mayo Clinic, Rochester, MN, USA
| | - Kamal Mahawar
- Department of Upper Gastrointestinal Surgery, South Tyneside and Sunderland NHS Foundation Trust, Sunderland, UK
| | - Asim Shabbir
- National University of Singapore, Singapore, Singapore
| | - Carel W le Roux
- Diabetes Complications Research Centre, University College Dublin, Dublin, Ireland
| | - Giovanni Targher
- Department of Medicine, University of Verona, Verona, Italy
- Metabolic Diseases Research Unit, IRCCS Sacro Cuore - Don Calabria Hospital, Negrar di Valpolicella, Italy
| | - Christopher D Byrne
- Southampton National Institute for Health and Care Research Biomedical Research Centre, University Hospital Southampton, and University of Southampton, Southampton General Hospital, Southampton, UK
| | - Yusuf Yilmaz
- Department of Gastroenterology, School of Medicine, Recep Tayyip Erdoğan University, Rize, Turkey
| | - Luca Valenti
- Department of Pathophysiology and Transplantation, Università Degli Studi di Milano, Milan, Italy
- Precision Medicine, Biological Resource Center, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico Milano, Milan, Italy
| | - Giada Sebastiani
- Division of Gastroenterology and Hepatology, Chronic Viral Illness Service, McGill University Health Centre, Royal Victoria Hospital, Montreal, Canada
| | | | - Hannah Xiaoyan Hui
- School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Nasser Sakran
- Department of General Surgery, Holy Family Hospital, Nazareth, Israel
- The Azrieli Faculty of Medicine, Bar-Ilan University, Ramat Gan, Israel
| | - Manoel Galvao Neto
- Orlando Health Weight Loss and Bariatric Surgery Institute, Orlando, USA
- Mohak Bariatric and Robotic Center, Indore, India
| | - Mohammad Kermansaravi
- Department of Surgery, Division of Minimally Invasive and Bariatric Surgery, School of Medicine, Hazrat-E Fatemeh Hospital, Iran University of Medical Sciences, Tehran, Iran
| | - Lilian Kow
- Department GI Surgery, Flinders University South Australia, Adelaide, Australia
| | - Yosuke Seki
- Weight Loss and Metabolic Surgery Centre, Yotsuya Medical Cube, Tokyo, Japan
| | | | - Jerry Dang
- Digestive Disease Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Ricardo V Cohen
- The Center for Obesity and Diabetes, Hospital Alemao Oswaldo Cruz, Sao Paulo, Brazil
| | - Christine Stier
- Department of MBS and Bariatric Endoscopy, University Hospital Mannheim, Heidelberg University, Mannheim, Baden-Wuerttenberg, Germany
| | - Salman AlSabah
- Department of Surgery, Kuwait University, Kuwait, Kuwait
| | - Rodolfo J Oviedo
- Nacogdoches Medical Center, Nacogdoches, TX, USA
- University of Houston Tilman J. Fertitta Family College of Medicine, Houston, TX, USA
- Sam Houston State University College of Osteopathic Medicine, Conroe, TX, USA
| | - Sonja Chiappetta
- Bariatric and Metabolic Surgery Unit, Department for General and Laparoscopic Surgery, Ospedale Evangelico Betania, Naples, Italy
| | - Chetan Parmar
- Department of Surgery, Whittington Hospital,, University College London, London, UK
| | - Wah Yang
- Department of Metabolic and Bariatric Surgery, The First Affiliated Hospital of Jinan University, No. 613 Huangpu Avenue West, Guangzhou, China.
| |
Collapse
|
28
|
Rabiu L, Zhang P, Afolabi LO, Saliu MA, Dabai SM, Suleiman RB, Gidado KI, Ige MA, Ibrahim A, Zhang G, Wan X. Immunological dynamics in MASH: from landscape analysis to therapeutic intervention. J Gastroenterol 2024; 59:1053-1078. [PMID: 39400718 DOI: 10.1007/s00535-024-02157-0] [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: 07/24/2024] [Accepted: 10/01/2024] [Indexed: 10/15/2024]
Abstract
Metabolic dysfunction-associated steatohepatitis (MASH), previously known as nonalcoholic steatohepatitis (NASH), is a multifaceted liver disease characterized by inflammation and fibrosis that develops from simple steatosis. Immune and inflammatory pathways have a central role in the pathogenesis of MASH, yet, how to target immune pathways to treat MASH remains perplexed. This review emphasizes the intricate role that immune cells play in the etiology and pathophysiology of MASH and highlights their significance as targets for therapeutic approaches. It discusses both current strategies and novel therapies aimed at modulating the immune response in MASH. It also highlights challenges in liver-specific drug delivery, potential off-target effects, and difficulties in targeting diverse immune cell populations within the liver. This review is a comprehensive resource that integrates current knowledge with future perspectives in the evolving field of MASH, with the goal of driving forward progress in medical therapies designed to treat this complex liver disease.
Collapse
Affiliation(s)
- Lawan Rabiu
- Center for Protein and Cell-Based Drugs, Institute of Biomedicine and Biotechnology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, 518055, People's Republic of China
- University of Chinese Academy of Sciences, Beijing, 100864, People's Republic of China
- Federal University Dutse, Jigawa, Nigeria
| | - Pengchao Zhang
- Center for Protein and Cell-Based Drugs, Institute of Biomedicine and Biotechnology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, 518055, People's Republic of China
- University of Chinese Academy of Sciences, Beijing, 100864, People's Republic of China
| | - Lukman O Afolabi
- Department of Pediatrics, Indiana University School of Medicine, 1234 Notre Dame Ave, S Bend, IN, 46617, USA
| | - Muhammad A Saliu
- Center for Protein and Cell-Based Drugs, Institute of Biomedicine and Biotechnology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, 518055, People's Republic of China
- University of Chinese Academy of Sciences, Beijing, 100864, People's Republic of China
| | - Salisu M Dabai
- Center for Protein and Cell-Based Drugs, Institute of Biomedicine and Biotechnology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, 518055, People's Republic of China
- University of Chinese Academy of Sciences, Beijing, 100864, People's Republic of China
| | - Rabiatu B Suleiman
- Center for Protein and Cell-Based Drugs, Institute of Biomedicine and Biotechnology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, 518055, People's Republic of China
- University of Chinese Academy of Sciences, Beijing, 100864, People's Republic of China
| | - Khalid I Gidado
- Center for Protein and Cell-Based Drugs, Institute of Biomedicine and Biotechnology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, 518055, People's Republic of China
- University of Chinese Academy of Sciences, Beijing, 100864, People's Republic of China
| | - Mark A Ige
- Center for Protein and Cell-Based Drugs, Institute of Biomedicine and Biotechnology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, 518055, People's Republic of China
- University of Chinese Academy of Sciences, Beijing, 100864, People's Republic of China
| | - Abdulrahman Ibrahim
- Center for Protein and Cell-Based Drugs, Institute of Biomedicine and Biotechnology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, 518055, People's Republic of China
- University of Chinese Academy of Sciences, Beijing, 100864, People's Republic of China
| | - Guizhong Zhang
- Center for Protein and Cell-Based Drugs, Institute of Biomedicine and Biotechnology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, 518055, People's Republic of China.
- University of Chinese Academy of Sciences, Beijing, 100864, People's Republic of China.
| | - Xiaochun Wan
- Center for Protein and Cell-Based Drugs, Institute of Biomedicine and Biotechnology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, 518055, People's Republic of China.
- University of Chinese Academy of Sciences, Beijing, 100864, People's Republic of China.
| |
Collapse
|
29
|
Vissers G, Giacomozzi M, Verdurmen W, Peek R, Nap A. The role of fibrosis in endometriosis: a systematic review. Hum Reprod Update 2024; 30:706-750. [PMID: 39067455 PMCID: PMC11532625 DOI: 10.1093/humupd/dmae023] [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: 03/15/2024] [Revised: 06/04/2024] [Indexed: 07/30/2024] Open
Abstract
BACKGROUND Fibrosis is an important pathological feature of endometriotic lesions of all subtypes. Fibrosis is present in and around endometriotic lesions, and a central role in its development is played by myofibroblasts, which are cells derived mainly after epithelial-to-mesenchymal transition (EMT) and fibroblast-to-myofibroblast transdifferentiation (FMT). Transforming growth factor-β (TGF-β) has a key role in this myofibroblastic differentiation. Myofibroblasts deposit extracellular matrix (ECM) and have contracting abilities, leading to a stiff micro-environment. These aspects are hypothesized to be involved in the origin of endometriosis-associated pain. Additionally, similarities between endometriosis-related fibrosis and other fibrotic diseases, such as systemic sclerosis or lung fibrosis, indicate that targeting fibrosis could be a potential therapeutic strategy for non-hormonal therapy for endometriosis. OBJECTIVE AND RATIONALE This review aims to summarize the current knowledge and to highlight the knowledge gaps about the role of fibrosis in endometriosis. A comprehensive literature overview about the role of fibrosis in endometriosis can improve the efficiency of fibrosis-oriented research in endometriosis. SEARCH METHODS A systematic literature search was performed in three biomedical databases using search terms for 'endometriosis', 'fibrosis', 'myofibroblasts', 'collagen', and 'α-smooth muscle actin'. Original studies were included if they reported about fibrosis and endometriosis. Both preclinical in vitro and animal studies, as well as research concerning human subjects were included. OUTCOMES Our search yielded 3441 results, of which 142 studies were included in this review. Most studies scored a high to moderate risk of bias according to the bias assessment tools. The studies were divided in three categories: human observational studies, experimental studies with human-derived material, and animal studies. The observational studies showed details about the histologic appearance of fibrosis in endometriosis and the co-occurrence of nerves and immune cells in lesions. The in vitro studies identified several pro-fibrotic pathways in relation to endometriosis. The animal studies mainly assessed the effect of potential therapeutic strategies to halt or regress fibrosis, for example targeting platelets or mast cells. WIDER IMPLICATIONS This review shows the central role of fibrosis and its main cellular driver, the myofibroblast, in endometriosis. Platelets and TGF-β have a pivotal role in pro-fibrotic signaling. The presence of nerves and neuropeptides is closely associated with fibrosis in endometriotic lesions, and is likely a cause of endometriosis-associated pain. The process of fibrotic development after EMT and FMT shares characteristics with other fibrotic diseases, so exploring similarities in endometriosis with known processes in diseases like systemic sclerosis, idiopathic pulmonary fibrosis or liver cirrhosis is relevant and a promising direction to explore new treatment strategies. The close relationship with nerves appears rather unique for endometriosis-related fibrosis and is not observed in other fibrotic diseases. REGISTRATION NUMBER N/A.
Collapse
Affiliation(s)
- Guus Vissers
- Department of Obstetrics & Gynaecology, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Maddalena Giacomozzi
- Department of Obstetrics & Gynaecology, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Wouter Verdurmen
- Department of Medical BioSciences, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Ron Peek
- Department of Obstetrics & Gynaecology, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Annemiek Nap
- Department of Obstetrics & Gynaecology, Radboud University Medical Center, Nijmegen, The Netherlands
| |
Collapse
|
30
|
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 PMCID: PMC11653607 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 DiseasesThe Second Xiangya HospitalCentral South University139 Renmin Middle Rd, Furong DistrictChangshaHunan410011P. R. China
| | - Jiashi Gao
- Department of Infectious DiseasesThe Second Xiangya HospitalCentral South University139 Renmin Middle Rd, Furong DistrictChangshaHunan410011P. R. China
- Department of Molecular & Integrative PhysiologyUniversity of Michigan Medical SchoolNCRC 20–3843, 2800 Plymouth RoadAnn ArborMI48105USA
- Caswell Diabetes InstituteUniversity of Michigan Medical SchoolNCRC 20–3843, 2800 Plymouth RoadAnn ArborMI48105USA
| | - Meichan Yang
- Department of RadiologyGuangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences)Southern Medical University106 Zhongshan 2nd RoadGuangzhouGuangdong51008P. R. China
- Provincial Key Laboratory of Artificial Intelligence in Medical Image Analysis and ApplicationGuangzhouGuangdong51008P. R. China
| | - Gary Zhang
- Department of Molecular & Integrative PhysiologyUniversity of Michigan Medical SchoolNCRC 20–3843, 2800 Plymouth RoadAnn ArborMI48105USA
- Caswell Diabetes InstituteUniversity of Michigan Medical SchoolNCRC 20–3843, 2800 Plymouth RoadAnn ArborMI48105USA
| | - Lei Yin
- Department of Molecular & Integrative PhysiologyUniversity of Michigan Medical SchoolNCRC 20–3843, 2800 Plymouth RoadAnn ArborMI48105USA
- Caswell Diabetes InstituteUniversity of Michigan Medical SchoolNCRC 20–3843, 2800 Plymouth RoadAnn ArborMI48105USA
| | - Xin Tong
- Department of Molecular & Integrative PhysiologyUniversity of Michigan Medical SchoolNCRC 20–3843, 2800 Plymouth RoadAnn ArborMI48105USA
- Caswell Diabetes InstituteUniversity of Michigan Medical SchoolNCRC 20–3843, 2800 Plymouth RoadAnn ArborMI48105USA
| |
Collapse
|
31
|
Aldroubi BG, Najjar JA, Youssef TS, Rizk CE, Abuamreh BA, Aramouni K, Ghadieh HE, Najjar SM. Cell-specific regulation of insulin action and hepatic fibrosis by CEACAM1. METABOLISM AND TARGET ORGAN DAMAGE 2024; 4:34. [PMID: 39640841 PMCID: PMC11619085 DOI: 10.20517/mtod.2024.48] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/07/2024]
Abstract
The incidence of metabolic dysfunction-associated steatotic liver disease (MASLD) has reached an epidemic rise worldwide. The disease is a constellation of a broad range of metabolic and histopathologic abnormalities. It begins with hepatic steatosis and progresses to metabolic dysfunction-associated steatohepatitis (MASH), including hepatic fibrosis, apoptosis, and cell injury. Despite ample research effort, the pathogenesis of the disease has not been fully delineated. Whereas insulin resistance is implicated in the early stages of the disease, its role in hepatic fibrosis remains controversial. We have focused our studies on the role of carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) in hepatocytes and endothelial cells in the metabolic and histopathological dysregulation in MASH. Patients with MASH exhibit lower hepatic CEACAM1 with a progressive decline in hepatocytes and endothelial cells as the fibrosis stage advances. In mice, conditional deletion of CEACAM1 in hepatocytes impairs insulin clearance to cause hyperinsulinemia-driven insulin resistance with steatohepatitis and hepatic fibrosis even when mice are fed a regular chow diet. In contrast, its conditional deletion in endothelial cells causes inflammation-driven hepatic fibrosis without adversely affecting metabolism (mice remain insulin-sensitive and do not develop hepatic steatosis). Thus, this review provides in vivo evidence that supports or discards the role of insulin resistance in liver injury and hepatic fibrosis.
Collapse
Affiliation(s)
- Basel G. Aldroubi
- Department of Biomedical Sciences, Heritage College of Osteopathic Medicine, Ohio University, Athens, OH 45701, USA
| | - John A. Najjar
- Department of Pathology, College of Medicine and Life Sciences, University of Toledo, Toledo, OH 43614, USA
| | - Tya S. Youssef
- Department of Biomedical Sciences, Faculty of Medicine and Medical Sciences, University of Balamand, Al-Koura PO box 100 Tripoli, Kalhat, Lebanon
| | - Carl E. Rizk
- Department of Biomedical Sciences, Faculty of Medicine and Medical Sciences, University of Balamand, Al-Koura PO box 100 Tripoli, Kalhat, Lebanon
| | - Basil A.M. Abuamreh
- Department of Biomedical Sciences, Heritage College of Osteopathic Medicine, Ohio University, Athens, OH 45701, USA
| | - Karl Aramouni
- Department of Medicine, Faculty of Medicine, American University of Beirut, Beirut 1107-2020, Lebanon
| | - Hilda E. Ghadieh
- Department of Biomedical Sciences, Faculty of Medicine and Medical Sciences, University of Balamand, Al-Koura PO box 100 Tripoli, Kalhat, Lebanon
| | - Sonia M. Najjar
- Department of Biomedical Sciences, Heritage College of Osteopathic Medicine, Ohio University, Athens, OH 45701, USA
- Diabetes Institute, Heritage College of Osteopathic Medicine, Ohio University, Athens, OH 43614, USA
| |
Collapse
|
32
|
Chen C, Zhou X, Cheng W, Li X, Zhang B, Tu J, Meng J, Peng Y, Duan X, Yu Q, Tan X. Design, synthesis and FXR partial agonistic activity of anthranilic acid derivatives bearing aryloxy moiety as therapeutic agents for metabolic dysfunction-associated steatohepatitis. Bioorg Chem 2024; 153:107940. [PMID: 39515132 DOI: 10.1016/j.bioorg.2024.107940] [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: 09/03/2024] [Revised: 10/26/2024] [Accepted: 11/02/2024] [Indexed: 11/16/2024]
Abstract
Farnesoid X receptor (FXR) is considered a promising therapeutic target for the treatment of metabolic dysfunction-associated steatohepatitis (MASH). Increasing evidence suggests that targeting FXR with full agonists may lead to side effects. FXR partial agonists, which moderately activate FXR signaling, are emerging as a feasible approach to mitigate side effects and address MASH. Herein, a series of novel anthranilic acid derivatives bearing aryloxy moiety were designed and synthesized using a hybrid strategy from the previously identified FXR partial agonists DM175 and AIV-25. Particularly, compound 26 exhibited potent FXR partial agonistic activity in a dual-luciferase reporter gene assay with an EC50 value of 0.09 ± 0.02 µM (75.13 % maximum efficacy relative to OCA). In the MASH mice model, compound 26 significantly ameliorated the pathological features of the liver, including steatosis, inflammation, and fibrosis. In addition, compound 26 displayed high selectivity, good oral bioavailability, high liver distribution, as well as an acceptable safety profile. Molecular simulation studies showed that compound 26 fitted well with the binding site of FXR. Collectively, these findings demonstrated that compound 26 might serve as a promising candidate targeting FXR for MASH treatment.
Collapse
Affiliation(s)
- Cong Chen
- Guangxi Key Laboratory of Drug Discovery and Optimization, College of Pharmacy, Guilin Medical University, Guilin 541199, China; Guangxi Key Laboratory of Environmental Exposure Omics and Life Cycle Health, College of Public Health, Guilin Medical University, Guilin 541199, China
| | - Xianghui Zhou
- Guangxi Key Laboratory of Drug Discovery and Optimization, College of Pharmacy, Guilin Medical University, Guilin 541199, China; Department of Pharmacy, Yunfu People's Hospital, Yunfu 527300, China
| | - Wa Cheng
- Guangxi Key Laboratory of Drug Discovery and Optimization, College of Pharmacy, Guilin Medical University, Guilin 541199, China
| | - Xin Li
- School of Life Sciences, Guangzhou University, Guangzhou 510006, China
| | - Bing Zhang
- Guangxi Key Laboratory of Drug Discovery and Optimization, College of Pharmacy, Guilin Medical University, Guilin 541199, China
| | - Jiaojiao Tu
- Guangxi Key Laboratory of Drug Discovery and Optimization, College of Pharmacy, Guilin Medical University, Guilin 541199, China
| | - Jieyun Meng
- Guangxi Key Laboratory of Drug Discovery and Optimization, College of Pharmacy, Guilin Medical University, Guilin 541199, China
| | - Yanfen Peng
- Guangxi Key Laboratory of Drug Discovery and Optimization, College of Pharmacy, Guilin Medical University, Guilin 541199, China
| | - Xiaoqun Duan
- Guangxi Key Laboratory of Drug Discovery and Optimization, College of Pharmacy, Guilin Medical University, Guilin 541199, China.
| | - Qiming Yu
- Guangxi Key Laboratory of Environmental Exposure Omics and Life Cycle Health, College of Public Health, Guilin Medical University, Guilin 541199, China.
| | - Xiangduan Tan
- Guangxi Key Laboratory of Drug Discovery and Optimization, College of Pharmacy, Guilin Medical University, Guilin 541199, China.
| |
Collapse
|
33
|
Pilling D, Martinez TC, Gomer RH. Inhibition of CCl4-induced liver inflammation and fibrosis by a NEU3 inhibitor. PLoS One 2024; 19:e0308060. [PMID: 39570922 PMCID: PMC11581222 DOI: 10.1371/journal.pone.0308060] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2024] [Accepted: 09/26/2024] [Indexed: 11/24/2024] Open
Abstract
Sialic acids are located on the ends of many glycoconjugates and are cleaved off by enzymes called sialidases (neuraminidases). Upregulation of neuraminidase 3 (NEU3) is associated with intestinal inflammation and colitis, neuroinflammation, and lung fibrosis. Genetic ablation of NEU3 or pharmacological inhibition of NEU3 reduces lung fibrosis in mice. To determine if inhibiting NEU3 can inhibit liver fibrosis in the commonly-used CCl4 model, in this report, we examined the effects of injections of the NEU3 inhibitor 2-acetyl pyridine (2AP). 2AP inhibited CCl4-induced weight loss in female but not male mice. 2AP attenuated CCl4-induced liver inflammation and fibrosis in male and female mice, but did not affect CCl4-induced steatosis. After CCl4 treatment, female but not male mice had significant increases in liver neutrophils, and 2AP attenuated this response. 2AP also reversed CCl4-induced liver desialylation and CCl4-induced increased expression of NEU3. Patients with pulmonary fibrosis have increased desialylation of some serum proteins, and elevated serum levels of NEU3. We find that sera from patients with nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) have elevated desialylation of a serum protein and patients with NAFLD have increased levels of NEU3. These data suggest that elevated levels of NEU3 may be associated with liver inflammation and fibrosis, and that in mice this is ameliorated by injections of a NEU3 inhibitor.
Collapse
Affiliation(s)
- Darrell Pilling
- Department of Biology, Texas A&M University, College Station, Texas, United States of America
| | - Trevor C. Martinez
- Department of Biology, Texas A&M University, College Station, Texas, United States of America
| | - Richard H. Gomer
- Department of Biology, Texas A&M University, College Station, Texas, United States of America
| |
Collapse
|
34
|
Yamauchi Y, Mieno H, Suetsugu H, Watanabe H, Nakaya M. Elevated PRELP expression in heart and liver fibrosis promotes collagen production. Biochem Biophys Res Commun 2024; 734:150785. [PMID: 39369540 DOI: 10.1016/j.bbrc.2024.150785] [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: 08/27/2024] [Accepted: 10/01/2024] [Indexed: 10/08/2024]
Abstract
Fibrosis results from the excessive production of extracellular matrix proteins by myofibroblasts. It has recently been reported that in the heart, myofibroblasts develop chondrocyte-like properties following myocardial infarction as fibrosis progresses and tissues stiffen. However, the nature of these chondrocyte-like myofibroblasts remains unclear. In this study, we found that the expression of the proline- and arginine-rich end leucine-rich repeat protein (PRELP) was upregulated in hearts and livers stiffened by fibrosis with chronic inflammation. Moreover, we established that Prelp was specifically expressed in chondrocyte-like myofibroblasts. Prelp expression was found to be regulated by the transcription factor SOX9, and in cardiac and liver myofibroblasts, Prelp-knockdown was observed to reduce collagen expression. These findings reveal that PRELP is specifically expressed in chondrocyte-like myofibroblasts and that it promotes collagen production. PRELP could thus serve as a novel therapeutic target for treating fibrosis.
Collapse
Affiliation(s)
- Yuto Yamauchi
- Department of Disease Control, Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
| | - Hiroki Mieno
- Department of Disease Control, Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
| | - Haruna Suetsugu
- Department of Disease Control, Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
| | - Hayato Watanabe
- Department of Disease Control, Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
| | - Michio Nakaya
- Department of Disease Control, Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan; Department of Disease Control, Research Institute of Environmental Medicine, Nagoya University, Nagoya, 464-8601, Japan.
| |
Collapse
|
35
|
Li S, Chen F, Liu M, Zhang Y, Xu J, Li X, Shang Z, Huang S, Song S, Tu C. Knockdown of hepatic mitochondrial calcium uniporter mitigates MASH and fibrosis in mice. Cell Biosci 2024; 14:135. [PMID: 39523398 PMCID: PMC11550531 DOI: 10.1186/s13578-024-01315-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2024] [Accepted: 10/21/2024] [Indexed: 11/16/2024] Open
Abstract
BACKGROUND Mitochondrial calcium uniporter (MCU) plays pleiotropic roles in cellular physiology and pathology that contributes to a variety of diseases, but the role and potential mechanism of MCU in the pathogenesis of metabolic dysfunction-associated steatohepatitis (MASH) remain poorly understood. METHODS AND RESULTS Here, hepatic knockdown of MCU in C57BL/6J mice was achieved by tail vein injection of AAV8-mediated the CRISPR/Cas9. Mice were fed a Choline-deficient, L-amino acid-defined high-fat diet (CDAHFD) for 8 weeks to induce MASH and fibrosis. We find that expression of MCU enhanced in MASH livers of humans and mice. MCU knockdown robustly limits lipid droplet accumulation, steatosis, inflammation, and hepatocyte apoptotic death during MASH development both in vivo in mice and in vitro in cellular models. MCU-deficient mice strikingly mitigate MASH-related fibrosis. Moreover, the protective effects of MCU knockdown against MASH progression are accompanied by a reduced level of mitochondrial calcium, limiting hepatic oxidative stress, and attenuating mitochondrial dysfunction. Mechanically, RNA sequencing analysis and protein immunoblotting indicate that knockdown MCU inhibited the Hippo/YAP pathway activation and restored the AMP-activated protein kinase (AMPK) activity during MASH development both in vitro and in vivo. CONCLUSIONS MCU is up-regulated in MASH livers in humans and mice; and hepatic MCU knockdown protects against diet-induced MASH and fibrosis in mice. Thus, targeting MCU may represent a novel therapeutic strategy for MASH and fibrosis.
Collapse
Affiliation(s)
- Shuyu Li
- Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Fangyuan Chen
- Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Min Liu
- Department of Gastroenterology, Shanghai Public Health Clinical Center, Fudan University, Shanghai, 201508, China
| | - Yajun Zhang
- Department of Gastroenterology, Shanghai Public Health Clinical Center, Fudan University, Shanghai, 201508, China
| | - Jingjing Xu
- Department of Pathology, Shanghai Public Health Clinical Center, Fudan University, Shanghai, 201508, China
| | - Xi Li
- Department of Geriatrics, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Zhiyin Shang
- Department of Gastroenterology, Shanghai Public Health Clinical Center, Fudan University, Shanghai, 201508, China
| | - Shaoping Huang
- Department of Gastroenterology, Shanghai Public Health Clinical Center, Fudan University, Shanghai, 201508, China
| | - Shu Song
- Department of Pathology, Shanghai Public Health Clinical Center, Fudan University, Shanghai, 201508, China.
| | - Chuantao Tu
- Department of Gastroenterology, Shanghai Public Health Clinical Center, Fudan University, Shanghai, 201508, China.
| |
Collapse
|
36
|
Arto C, Rusu EC, Clavero-Mestres H, Barrientos-Riosalido A, Bertran L, Mahmoudian R, Aguilar C, Riesco D, Chicote JU, Parada D, Martínez S, Sabench F, Richart C, Auguet T. Metabolic profiling of tryptophan pathways: Implications for obesity and metabolic dysfunction-associated steatotic liver disease. Eur J Clin Invest 2024; 54:e14279. [PMID: 38940215 DOI: 10.1111/eci.14279] [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: 12/22/2023] [Accepted: 06/12/2024] [Indexed: 06/29/2024]
Abstract
BACKGROUND AND AIMS The rise in obesity highlights the need for improved therapeutic strategies, particularly in addressing metabolic dysfunction-associated steatotic liver disease (MASLD). We aim to assess the role of tryptophan metabolic pathways in the pathogenesis of obesity and in the different histological stages of MASLD. MATERIALS AND METHODS We used ultra-high performance liquid chromatography to quantify circulating levels of 15 tryptophan-related metabolites from the kynurenine, indole and serotonin pathways. A cohort of 76 subjects was analysed, comprising 18 subjects with normal weight and 58 with morbid obesity, these last being subclassified into normal liver (NL), simple steatosis (SS) and metabolic dysfunction-associated steatohepatitis (MASH). Then, we conducted gene expression analysis of hepatic IDO-1 and kynyrenine-3-monooxygenase (KMO). RESULTS Key findings in obesity revealed a distinct metabolic signature characterized by a higher concentration of different kynurenine-related metabolites, a decrease in indole-3-acetic acid and indole-3-propionic acid, and an alteration in the serotonin pathway. Elevated tryptophan levels were associated with MASLD presence (37.659 (32.577-39.823) μM of tryptophan in NL subjects; 41.522 (38.803-45.276) μM in patients with MASLD). Overall, pathway fluxes demonstrated an induction of tryptophan catabolism via the serotonin pathway in SS subjects and into the kynurenine pathway in MASH. We found decreased IDO-1 and KMO hepatic expression in NL compared to SS. CONCLUSIONS We identified a distinctive metabolic signature in obesity marked by changes in tryptophan catabolic pathways, discernible through altered metabolite profiles. We observed stage-specific alterations in tryptophan catabolism fluxes in MASLD, highlighting the potential utility of targeting these pathways in therapeutic interventions.
Collapse
Affiliation(s)
- Carmen Arto
- Servei Medicina Interna, Hospital Sant Pau i Santa Tecla de Tarragona, Tarragona, Spain
| | - Elena Cristina Rusu
- Departament de Medicina i Cirurgia, Grup de Recerca GEMMAIR (AGAUR)-Medicina Aplicada (URV), Universitat Rovira i Virgili (URV), Institut d'Investigació Sanitària Pere Virgili (IISPV), Tarragona, Spain
| | - Helena Clavero-Mestres
- Departament de Medicina i Cirurgia, Grup de Recerca GEMMAIR (AGAUR)-Medicina Aplicada (URV), Universitat Rovira i Virgili (URV), Institut d'Investigació Sanitària Pere Virgili (IISPV), Tarragona, Spain
| | - Andrea Barrientos-Riosalido
- Departament de Medicina i Cirurgia, Grup de Recerca GEMMAIR (AGAUR)-Medicina Aplicada (URV), Universitat Rovira i Virgili (URV), Institut d'Investigació Sanitària Pere Virgili (IISPV), Tarragona, Spain
| | - Laia Bertran
- Departament de Medicina i Cirurgia, Grup de Recerca GEMMAIR (AGAUR)-Medicina Aplicada (URV), Universitat Rovira i Virgili (URV), Institut d'Investigació Sanitària Pere Virgili (IISPV), Tarragona, Spain
| | - Razieh Mahmoudian
- Departament de Medicina i Cirurgia, Grup de Recerca GEMMAIR (AGAUR)-Medicina Aplicada (URV), Universitat Rovira i Virgili (URV), Institut d'Investigació Sanitària Pere Virgili (IISPV), Tarragona, Spain
| | - Carmen Aguilar
- Departament de Medicina i Cirurgia, Grup de Recerca GEMMAIR (AGAUR)-Medicina Aplicada (URV), Universitat Rovira i Virgili (URV), Institut d'Investigació Sanitària Pere Virgili (IISPV), Tarragona, Spain
| | - David Riesco
- Departament de Medicina i Cirurgia, Grup de Recerca GEMMAIR (AGAUR)-Medicina Aplicada (URV), Universitat Rovira i Virgili (URV), Institut d'Investigació Sanitària Pere Virgili (IISPV), Tarragona, Spain
- Servei Medicina Interna, Hospital Universitari de Tarragona Joan XXIII, Tarragona, Spain
| | - Javier Ugarte Chicote
- Departament de Medicina i Cirurgia, Grup de Recerca GEMMAIR (AGAUR)-Medicina Aplicada (URV), Universitat Rovira i Virgili (URV), Institut d'Investigació Sanitària Pere Virgili (IISPV), Tarragona, Spain
- Servei Anatomia Patològica, Hospital Universitari de Tarragona Joan XXIII, Tarragona, Spain
| | - David Parada
- Departament de Medicina i Cirurgia, Grup de Recerca GEMMAIR (AGAUR)-Medicina Aplicada (URV), Universitat Rovira i Virgili (URV), Institut d'Investigació Sanitària Pere Virgili (IISPV), Tarragona, Spain
- Servei Anatomia Patològica, Hospital Sant Joan de Reus, Avinguda Doctor Josep Laporte, Reus, Spain
| | - Salomé Martínez
- Departament de Medicina i Cirurgia, Grup de Recerca GEMMAIR (AGAUR)-Medicina Aplicada (URV), Universitat Rovira i Virgili (URV), Institut d'Investigació Sanitària Pere Virgili (IISPV), Tarragona, Spain
- Servei Anatomia Patològica, Hospital Universitari de Tarragona Joan XXIII, Tarragona, Spain
| | - Fàtima Sabench
- Departament de Medicina i Cirurgia, Grup de Recerca GEMMAIR (AGAUR)-Medicina Aplicada (URV), Universitat Rovira i Virgili (URV), Institut d'Investigació Sanitària Pere Virgili (IISPV), Tarragona, Spain
- Departament de Medicina i Cirurgia, Servei de Cirurgia, Hospital Sant Joan de Reus, URV, IISPV, Avinguda Doctor Josep Laporte, Reus, Spain
| | - Cristóbal Richart
- Departament de Medicina i Cirurgia, Grup de Recerca GEMMAIR (AGAUR)-Medicina Aplicada (URV), Universitat Rovira i Virgili (URV), Institut d'Investigació Sanitària Pere Virgili (IISPV), Tarragona, Spain
| | - Teresa Auguet
- Departament de Medicina i Cirurgia, Grup de Recerca GEMMAIR (AGAUR)-Medicina Aplicada (URV), Universitat Rovira i Virgili (URV), Institut d'Investigació Sanitària Pere Virgili (IISPV), Tarragona, Spain
- Servei Medicina Interna, Hospital Universitari de Tarragona Joan XXIII, Tarragona, Spain
| |
Collapse
|
37
|
Xu R, Vujić N, Bianco V, Reinisch I, Kratky D, Krstic J, Prokesch A. Lipid-associated macrophages between aggravation and alleviation of metabolic diseases. Trends Endocrinol Metab 2024; 35:981-995. [PMID: 38705759 DOI: 10.1016/j.tem.2024.04.009] [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: 01/20/2024] [Revised: 04/09/2024] [Accepted: 04/10/2024] [Indexed: 05/07/2024]
Abstract
Lipid-associated macrophages (LAMs) are phagocytic cells with lipid-handling capacity identified in various metabolic derangements. During disease development, they locate to atherosclerotic plaques, adipose tissue (AT) of individuals with obesity, liver lesions in steatosis and steatohepatitis, and the intestinal lamina propria. LAMs can also emerge in the metabolically demanding microenvironment of certain tumors. In this review, we discuss major questions regarding LAM recruitment, differentiation, and self-renewal, and, ultimately, their acute and chronic functional impact on the development of metabolic diseases. Further studies need to clarify whether and under which circumstances LAMs drive disease progression or resolution and how their phenotype can be modulated to ameliorate metabolic disorders.
Collapse
Affiliation(s)
- Ruonan Xu
- Gottfried Schatz Research Center for Cell Signaling, Metabolism, and Aging, Division of Cell Biology, Histology, and Embryology, Medical University of Graz, Graz, Austria
| | - Nemanja Vujić
- Gottfried Schatz Research Center, Molecular Biology and Biochemistry, Medical University of Graz, Graz, Austria
| | - Valentina Bianco
- Gottfried Schatz Research Center, Molecular Biology and Biochemistry, Medical University of Graz, Graz, Austria
| | - Isabel Reinisch
- Institute of Food Nutrition and Health, Department of Health Sciences and Technology, Eidgenössische Technische Hochschule Zürich (ETH), Schwerzenbach, Switzerland
| | - Dagmar Kratky
- Gottfried Schatz Research Center, Molecular Biology and Biochemistry, Medical University of Graz, Graz, Austria; BioTechMed-Graz, Graz, Austria
| | - Jelena Krstic
- Gottfried Schatz Research Center for Cell Signaling, Metabolism, and Aging, Division of Cell Biology, Histology, and Embryology, Medical University of Graz, Graz, Austria; BioTechMed-Graz, Graz, Austria
| | - Andreas Prokesch
- Gottfried Schatz Research Center for Cell Signaling, Metabolism, and Aging, Division of Cell Biology, Histology, and Embryology, Medical University of Graz, Graz, Austria; BioTechMed-Graz, Graz, Austria.
| |
Collapse
|
38
|
Zhang M, Barroso E, Peña L, Rada P, Valverde ÁM, Wahli W, Palomer X, Vázquez-Carrera M. PPARβ/δ attenuates hepatic fibrosis by reducing SMAD3 phosphorylation and p300 levels via AMPK in hepatic stellate cells. Biomed Pharmacother 2024; 179:117303. [PMID: 39153437 DOI: 10.1016/j.biopha.2024.117303] [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: 06/05/2024] [Revised: 08/04/2024] [Accepted: 08/13/2024] [Indexed: 08/19/2024] Open
Abstract
The role of peroxisome proliferator-activated receptor (PPAR)β/δ in hepatic fibrosis remains a subject of debate. Here, we examined the effects of a PPARβ/δ agonist on the pathogenesis of liver fibrosis and the activation of hepatic stellate cells (HSCs), the main effector cells in liver fibrosis, in response to the pro-fibrotic stimulus transforming growth factor-β (TGF-β). The PPARβ/δ agonist GW501516 completely prevented glucose intolerance and peripheral insulin resistance, blocked the accumulation of collagen in the liver, and attenuated the expression of inflammatory and fibrogenic genes in mice fed a choline-deficient high-fat diet (CD-HFD). The antifibrogenic effect of GW501516 observed in the livers CD-HFD-fed mice could occur through an action on HSCs since primary HSCs isolated from Ppard-/- mice showed increased mRNA levels of the profibrotic gene Col1a1. Moreover, PPARβ/δ activation abrogated TGF-β1-mediated cell migration (an indicator of cell activation) in LX-2 cells (immortalized activated human HSCs). Likewise, GW501516 attenuated the phosphorylation of the main downstream intracellular protein target of TGF-β1, suppressor of mothers against decapentaplegic (SMAD)3, as well as the levels of the SMAD3 co-activator p300 via the activation of AMP-activated protein kinase (AMPK) and the subsequent inhibition of extracellular signal-regulated kinase-1/2 (ERK1/2) in LX-2 cells. Overall, these findings uncover a new mechanism by which the activation of AMPK by a PPARβ/δ agonist reduces TGF-β1-mediated activation of HSCs and fibrosis via the reduction of both SMAD3 phosphorylation and p300 levels.
Collapse
Affiliation(s)
- Meijian Zhang
- Department of Pharmacology, Toxicology and Therapeutic Chemistry, Faculty of Pharmacy and Food Sciences, Spain; Institute of Biomedicine of the University of Barcelona (IBUB), University of Barcelona, Barcelona 08028, Spain; Spanish Biomedical Research Center in Diabetes and Associated Metabolic Diseases (CIBERDEM)-Instituto de Salud Carlos III, Madrid 28029, Spain; Pediatric Research Institute-Hospital Sant Joan de Déu, Esplugues de Llobregat 08950, Spain
| | - Emma Barroso
- Department of Pharmacology, Toxicology and Therapeutic Chemistry, Faculty of Pharmacy and Food Sciences, Spain; Institute of Biomedicine of the University of Barcelona (IBUB), University of Barcelona, Barcelona 08028, Spain; Spanish Biomedical Research Center in Diabetes and Associated Metabolic Diseases (CIBERDEM)-Instituto de Salud Carlos III, Madrid 28029, Spain; Pediatric Research Institute-Hospital Sant Joan de Déu, Esplugues de Llobregat 08950, Spain.
| | - Lucía Peña
- Department of Pharmacology, Toxicology and Therapeutic Chemistry, Faculty of Pharmacy and Food Sciences, Spain; Institute of Biomedicine of the University of Barcelona (IBUB), University of Barcelona, Barcelona 08028, Spain; Spanish Biomedical Research Center in Diabetes and Associated Metabolic Diseases (CIBERDEM)-Instituto de Salud Carlos III, Madrid 28029, Spain; Pediatric Research Institute-Hospital Sant Joan de Déu, Esplugues de Llobregat 08950, Spain
| | - Patricia Rada
- Spanish Biomedical Research Center in Diabetes and Associated Metabolic Diseases (CIBERDEM)-Instituto de Salud Carlos III, Madrid 28029, Spain; Instituto de Investigaciones Biomédicas Sols-Morreale (CSIC/UAM), Madrid, Spain
| | - Ángela M Valverde
- Spanish Biomedical Research Center in Diabetes and Associated Metabolic Diseases (CIBERDEM)-Instituto de Salud Carlos III, Madrid 28029, Spain; Instituto de Investigaciones Biomédicas Sols-Morreale (CSIC/UAM), Madrid, Spain
| | - Walter Wahli
- Center for Integrative Genomics, University of Lausanne, Lausanne CH-1015, Switzerland; Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore 308232, Singapore; ToxAlim (Research Center in Food Toxicology), INRAE, UMR1331, Toulouse Cedex F-31300, France
| | - Xavier Palomer
- Department of Pharmacology, Toxicology and Therapeutic Chemistry, Faculty of Pharmacy and Food Sciences, Spain; Institute of Biomedicine of the University of Barcelona (IBUB), University of Barcelona, Barcelona 08028, Spain; Spanish Biomedical Research Center in Diabetes and Associated Metabolic Diseases (CIBERDEM)-Instituto de Salud Carlos III, Madrid 28029, Spain; Pediatric Research Institute-Hospital Sant Joan de Déu, Esplugues de Llobregat 08950, Spain
| | - Manuel Vázquez-Carrera
- Department of Pharmacology, Toxicology and Therapeutic Chemistry, Faculty of Pharmacy and Food Sciences, Spain; Institute of Biomedicine of the University of Barcelona (IBUB), University of Barcelona, Barcelona 08028, Spain; Spanish Biomedical Research Center in Diabetes and Associated Metabolic Diseases (CIBERDEM)-Instituto de Salud Carlos III, Madrid 28029, Spain; Pediatric Research Institute-Hospital Sant Joan de Déu, Esplugues de Llobregat 08950, Spain.
| |
Collapse
|
39
|
Ntambi JN, Kalyesubula M, Cootway D, Lewis SA, Phang YX, Liu Z, O'Neill LM, Lefers L, Huff H, Miller JR, Pegkou Christofi V, Anderson E, Aljohani A, Mutebi F, Dutta M, Patterson A, Ntambi JM. Hepatic stearoyl-CoA desaturase-1 deficiency induces fibrosis and hepatocellular carcinoma-related gene activation under a high carbohydrate low fat diet. Biochim Biophys Acta Mol Cell Biol Lipids 2024; 1869:159538. [PMID: 39067685 PMCID: PMC11323073 DOI: 10.1016/j.bbalip.2024.159538] [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: 03/11/2024] [Revised: 07/09/2024] [Accepted: 07/23/2024] [Indexed: 07/30/2024]
Abstract
Stearoyl-CoA desaturase-1 (SCD1) is a pivotal enzyme in lipogenesis, which catalyzes the synthesis of monounsaturated fatty acids (MUFA) from saturated fatty acids, whose ablation downregulates lipid synthesis, preventing steatosis and obesity. Yet deletion of SCD1 promotes hepatic inflammation and endoplasmic reticulum stress, raising the question of whether hepatic SCD1 deficiency promotes further liver damage, including fibrosis. To delineate whether SCD1 deficiency predisposes the liver to fibrosis, cirrhosis, and hepatocellular carcinoma (HCC), we employed in vivo SCD1 deficient global and liver-specific mouse models fed a high carbohydrate low-fat diet and in vitro established AML12 mouse cells. The absence of liver SCD1 remarkably increased the saturation of liver lipid species, as indicated by lipidomic analysis, and led to hepatic fibrosis. Consistently, SCD1 deficiency promoted hepatic gene expression related to fibrosis, cirrhosis, and HCC. Deletion of SCD1 increased the circulating levels of Osteopontin, known to be increased in fibrosis, and alpha-fetoprotein, often used as an early marker and a prognostic marker for patients with HCC. De novo lipogenesis or dietary supplementation of oleate, an SCD1-generated MUFA, restored the gene expression related to fibrosis, cirrhosis, and HCC. Although SCD1 deficient mice are protected against obesity and fatty liver, our results show that MUFA deprivation results in liver injury, including fibrosis, thus providing novel insights between MUFA insufficiency and pathways leading to fibrosis, cirrhosis, and HCC under lean non-steatotic conditions.
Collapse
Affiliation(s)
- Jayne-Norah Ntambi
- Department of Biochemistry, University of Wisconsin-Madison, 433 Babcock Drive, Madison, WI 53706, USA; Tufts Medical Center, Radiation Oncology, 800 Washington St., Box 359, Boston, MA 02111, USA
| | - Mugagga Kalyesubula
- Department of Biochemistry, University of Wisconsin-Madison, 433 Babcock Drive, Madison, WI 53706, USA
| | - Dylan Cootway
- Department of Biochemistry, University of Wisconsin-Madison, 433 Babcock Drive, Madison, WI 53706, USA
| | - Sarah A Lewis
- Department of Biochemistry, University of Wisconsin-Madison, 433 Babcock Drive, Madison, WI 53706, USA
| | - Yar Xin Phang
- Department of Biochemistry, University of Wisconsin-Madison, 433 Babcock Drive, Madison, WI 53706, USA
| | - Zhaojin Liu
- Department of Biochemistry, University of Wisconsin-Madison, 433 Babcock Drive, Madison, WI 53706, USA
| | - Lucas M O'Neill
- Department of Biochemistry, University of Wisconsin-Madison, 433 Babcock Drive, Madison, WI 53706, USA
| | - Lucas Lefers
- Department of Biochemistry, University of Wisconsin-Madison, 433 Babcock Drive, Madison, WI 53706, USA
| | - Hailey Huff
- Department of Biochemistry, University of Wisconsin-Madison, 433 Babcock Drive, Madison, WI 53706, USA
| | - Jacqueline Rose Miller
- Department of Biochemistry, University of Wisconsin-Madison, 433 Babcock Drive, Madison, WI 53706, USA
| | - Veronica Pegkou Christofi
- Department of Biochemistry, University of Wisconsin-Madison, 433 Babcock Drive, Madison, WI 53706, USA
| | - Ethan Anderson
- Department of Biochemistry, University of Wisconsin-Madison, 433 Babcock Drive, Madison, WI 53706, USA
| | - Ahmed Aljohani
- College of Science and Health Professions, King Saud Bin Abdulaziz University for Health Sciences, Riyadh 11564, Saudi Arabia; King Abdullah International Medical Research Center (KAIMRC), Riyadh 11564, Saudi Arabia
| | - Francis Mutebi
- School of Veterinary Medicine and Animal Resources, College of Veterinary Medicine, Animal Resources and Biosecurity, Makerere University, Kampala, Uganda
| | - Mainak Dutta
- Center for Molecular Toxicology and Carcinogenesis, Department of Veterinary & Biomedical Sciences, University Park, PA 16802, United States; Department of Biotechnology, Birla Institute of Technology and Science (BITS) Pilani Dubai Campus, Academic City, Dubai 345055, United Arab Emirates
| | - Andrew Patterson
- Center for Molecular Toxicology and Carcinogenesis, Department of Veterinary & Biomedical Sciences, University Park, PA 16802, United States; The Huck Institutes of the Life Sciences, Pennsylvania State University, University Park, PA 16802, United States
| | - James M Ntambi
- Department of Biochemistry, University of Wisconsin-Madison, 433 Babcock Drive, Madison, WI 53706, USA; Department of Nutritional Sciences, University of Wisconsin-Madison, 1415 Linden Drive, Madison, WI 53706, USA.
| |
Collapse
|
40
|
Muturi HT, Ghadieh HE, Asalla S, Lester SG, Belew GD, Zaidi S, Abdolahipour R, Shrestha AP, Portuphy AO, Stankus HL, Helal RA, Verhulst S, Duarte S, Zarrinpar A, van Grunsven LA, Friedman SL, Schwabe RF, Hinds TD, Kumarasamy S, Najjar SM. Conditional deletion of CEACAM1 in hepatic stellate cells causes their activation. Mol Metab 2024; 88:102010. [PMID: 39168268 PMCID: PMC11403062 DOI: 10.1016/j.molmet.2024.102010] [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: 02/22/2024] [Revised: 07/24/2024] [Accepted: 08/09/2024] [Indexed: 08/23/2024] Open
Abstract
OBJECTIVES Hepatic CEACAM1 expression declines with advanced hepatic fibrosis stage in patients with metabolic dysfunction-associated steatohepatitis (MASH). Global and hepatocyte-specific deletions of Ceacam1 impair insulin clearance to cause hepatic insulin resistance and steatosis. They also cause hepatic inflammation and fibrosis, a condition characterized by excessive collagen production from activated hepatic stellate cells (HSCs). Given the positive effect of PPARγ on CEACAM1 transcription and on HSCs quiescence, the current studies investigated whether CEACAM1 loss from HSCs causes their activation. METHODS We examined whether lentiviral shRNA-mediated CEACAM1 donwregulation (KD-LX2) activates cultured human LX2 stellate cells. We also generated LratCre + Cc1fl/fl mutants with conditional Ceacam1 deletion in HSCs and characterized their MASH phenotype. Media transfer experiments were employed to examine whether media from mutant human and murine HSCs activate their wild-type counterparts. RESULTS LratCre + Cc1fl/fl mutants displayed hepatic inflammation and fibrosis but without insulin resistance or hepatic steatosis. Their HSCs, like KD-LX2 cells, underwent myofibroblastic transformation and their media activated wild-type HSCs. This was inhibited by nicotinic acid treatment which blunted the release of IL-6 and fatty acids, both of which activate the epidermal growth factor receptor (EGFR) tyrosine kinase. Gefitinib inhibition of EGFR and its downstream NF-κB/IL-6/STAT3 inflammatory and MAPK-proliferation pathways also blunted HSCs activation in the absence of CEACAM1. CONCLUSIONS Loss of CEACAM1 in HSCs provoked their myofibroblastic transformation in the absence of insulin resistance and hepatic steatosis. This response is mediated by autocrine HSCs activation of the EGFR pathway that amplifies inflammation and proliferation.
Collapse
Affiliation(s)
- Harrison T Muturi
- Department of Biomedical Sciences, Heritage College of Osteopathic Medicine, Ohio University, Athens, OH, USA
| | - Hilda E Ghadieh
- Department of Biomedical Sciences, Heritage College of Osteopathic Medicine, Ohio University, Athens, OH, USA; Department of Biomedical Sciences, University of Balamand, Faculty of Medicine and Health Sciences, Al-Koura, Lebanon
| | - Suman Asalla
- Department of Biomedical Sciences, Heritage College of Osteopathic Medicine, Ohio University, Athens, OH, USA
| | - Sumona G Lester
- Center for Diabetes and Endocrine Research, College of Medicine and Life Sciences, University of Toledo, Toledo, OH, USA
| | - Getachew D Belew
- Department of Biomedical Sciences, Heritage College of Osteopathic Medicine, Ohio University, Athens, OH, USA
| | - Sobia Zaidi
- Department of Biomedical Sciences, Heritage College of Osteopathic Medicine, Ohio University, Athens, OH, USA
| | - Raziyeh Abdolahipour
- Department of Biomedical Sciences, Heritage College of Osteopathic Medicine, Ohio University, Athens, OH, USA
| | - Abhishek P Shrestha
- Department of Surgery, College of Medicine, University of Florida, Gainesville, FL, USA
| | - Agnes O Portuphy
- Department of Biomedical Sciences, Heritage College of Osteopathic Medicine, Ohio University, Athens, OH, USA
| | - Hannah L Stankus
- Department of Biomedical Sciences, Heritage College of Osteopathic Medicine, Ohio University, Athens, OH, USA
| | - Raghd Abu Helal
- Department of Biomedical Sciences, Heritage College of Osteopathic Medicine, Ohio University, Athens, OH, USA
| | - Stefaan Verhulst
- Liver Cell Biology Research Group, Vrije Universiteit Brussel, Brussel, Belgium
| | - Sergio Duarte
- Department of Surgery, College of Medicine, University of Florida, Gainesville, FL, USA
| | - Ali Zarrinpar
- Department of Surgery, College of Medicine, University of Florida, Gainesville, FL, USA
| | - Leo A van Grunsven
- Liver Cell Biology Research Group, Vrije Universiteit Brussel, Brussel, Belgium
| | - Scott L Friedman
- Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York 10029, NY, USA
| | - Robert F Schwabe
- Department of Medicine and the Digestive and Liver Disease Research Center, Columbia University New York, NY, USA
| | - Terry D Hinds
- Department of Pharmacology and Nutritional Sciences, University of Kentucky College of Medicine, Lexington, KY, USA
| | - Sivarajan Kumarasamy
- Department of Biomedical Sciences, Heritage College of Osteopathic Medicine, Ohio University, Athens, OH, USA
| | - Sonia M Najjar
- Department of Biomedical Sciences, Heritage College of Osteopathic Medicine, Ohio University, Athens, OH, USA; Diabetes Institute, Heritage College of Osteopathic Medicine, Ohio University, Athens, OH, USA.
| |
Collapse
|
41
|
Tung HC, Kim JW, Zhu J, Li S, Yan J, Liu Q, Koo I, Koshkin SA, Hao F, Zhong G, Xu M, Wang Z, Wang J, Huang Y, Xi Y, Cai X, Xu P, Ren S, Higashiyama T, Gonzalez FJ, Li S, Isoherranen N, Yang D, Ma X, Patterson AD, Xie W. Inhibition of heme-thiolate monooxygenase CYP1B1 prevents hepatic stellate cell activation and liver fibrosis by accumulating trehalose. Sci Transl Med 2024; 16:eadk8446. [PMID: 39321267 PMCID: PMC12084873 DOI: 10.1126/scitranslmed.adk8446] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2023] [Revised: 04/05/2024] [Accepted: 09/04/2024] [Indexed: 09/27/2024]
Abstract
Activation of extracellular matrix-producing hepatic stellate cells (HSCs) is a key event in liver fibrogenesis. We showed that the expression of the heme-thiolate monooxygenase cytochrome P450 1B1 (CYP1B1) was elevated in human and mouse fibrotic livers and activated HSCs. Systemic or HSC-specific ablation and pharmacological inhibition of CYP1B1 attenuated HSC activation and protected male but not female mice from thioacetamide (TAA)-, carbon tetrachloride (CCl4)-, or bile duct ligation (BDL)-induced liver fibrosis. Metabolomic analysis revealed an increase in the disaccharide trehalose in CYP1B1-deficient HSCs resulting from intestinal suppression of the trehalose-metabolizing enzyme trehalase, whose gene we found to be a target of RARα. Trehalose or its hydrolysis-resistant derivative lactotrehalose exhibited potent antifibrotic activity in vitro and in vivo by functioning as an HSC-specific autophagy inhibitor, which may account for the antifibrotic effect of CYP1B1 inhibition. Our study thus reveals an endobiotic function of CYP1B1 in liver fibrosis in males, mediated by liver-intestine cross-talk and trehalose. At the translational level, pharmacological inhibition of CYP1B1 or the use of trehalose/lactotrehalose may represent therapeutic strategies for liver fibrosis.
Collapse
Affiliation(s)
- Hung-Chun Tung
- Center for Pharmacogenetics and Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, PA 15261, USA
| | - Jong-Won Kim
- Center for Pharmacogenetics and Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, PA 15261, USA
| | - Junjie Zhu
- Center for Pharmacogenetics and Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, PA 15261, USA
| | - Sihan Li
- Center for Pharmacogenetics and Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, PA 15261, USA
| | - Jiong Yan
- Center for Pharmacogenetics and Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, PA 15261, USA
| | - Qing Liu
- Center for Molecular Toxicology and Carcinogenesis, Department of Veterinary and Biomedical Sciences, The Pennsylvania State University, University Park, PA 16802, USA
| | - Imhoi Koo
- Center for Molecular Toxicology and Carcinogenesis, Department of Veterinary and Biomedical Sciences, The Pennsylvania State University, University Park, PA 16802, USA
| | - Sergei A. Koshkin
- Center for Molecular Toxicology and Carcinogenesis, Department of Veterinary and Biomedical Sciences, The Pennsylvania State University, University Park, PA 16802, USA
| | - Fuhua Hao
- Center for Molecular Toxicology and Carcinogenesis, Department of Veterinary and Biomedical Sciences, The Pennsylvania State University, University Park, PA 16802, USA
| | - Guo Zhong
- Department of Pharmaceutics, School of Pharmacy, University of Washington, Seattle, WA 98195, USA
| | - Meishu Xu
- Center for Pharmacogenetics and Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, PA 15261, USA
| | - Zehua Wang
- Center for Pharmacogenetics and Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, PA 15261, USA
| | - Jingyuan Wang
- Center for Pharmacogenetics and Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, PA 15261, USA
| | - Yixian Huang
- Center for Pharmacogenetics and Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, PA 15261, USA
| | - Yue Xi
- Center for Pharmacogenetics and Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, PA 15261, USA
| | - Xinran Cai
- Center for Pharmacogenetics and Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, PA 15261, USA
| | - Pengfei Xu
- Center for Pharmacogenetics and Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, PA 15261, USA
| | - Songrong Ren
- Center for Pharmacogenetics and Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, PA 15261, USA
| | | | - Frank J. Gonzalez
- Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
| | - Song Li
- Center for Pharmacogenetics and Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, PA 15261, USA
| | - Nina Isoherranen
- Department of Pharmaceutics, School of Pharmacy, University of Washington, Seattle, WA 98195, USA
| | - Da Yang
- Center for Pharmacogenetics and Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, PA 15261, USA
| | - Xiaochao Ma
- Center for Pharmacogenetics and Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, PA 15261, USA
| | - Andrew D. Patterson
- Center for Molecular Toxicology and Carcinogenesis, Department of Veterinary and Biomedical Sciences, The Pennsylvania State University, University Park, PA 16802, USA
| | - Wen Xie
- Center for Pharmacogenetics and Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, PA 15261, USA
- Department of Pharmacology & Chemical Biology, University of Pittsburgh, Pittsburgh, PA 15261, USA
- Lead contact
| |
Collapse
|
42
|
Dubois V, Lefebvre P, Staels B, Eeckhoute J. Nuclear receptors: pathophysiological mechanisms and drug targets in liver disease. Gut 2024; 73:1562-1569. [PMID: 38862216 DOI: 10.1136/gutjnl-2023-331741] [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: 03/28/2024] [Accepted: 05/18/2024] [Indexed: 06/13/2024]
Abstract
Nuclear receptors (NRs) are ligand-dependent transcription factors required for liver development and function. As a consequence, NRs have emerged as attractive drug targets in a wide range of liver diseases. However, liver dysfunction and failure are linked to loss of hepatocyte identity characterised by deficient NR expression and activities. This might at least partly explain why several pharmacological NR modulators have proven insufficiently efficient to improve liver functionality in advanced stages of diseases such as metabolic dysfunction-associated steatotic liver disease (MASLD). In this perspective, we review the most recent advances in the hepatic NR field and discuss the contribution of multiomic approaches to our understanding of their role in the molecular organisation of an intricated transcriptional regulatory network, as well as in liver intercellular dialogues and interorgan cross-talks. We discuss the potential benefit of novel therapeutic approaches simultaneously targeting multiple NRs, which would not only reactivate the hepatic NR network and restore hepatocyte identity but also impact intercellular and interorgan interplays whose importance to control liver functions is further defined. Finally, we highlight the need of considering individual parameters such as sex and disease stage in the development of NR-based clinical strategies.
Collapse
Affiliation(s)
- Vanessa Dubois
- Basic and Translational Endocrinology (BaTE), Department of Basic and Applied Medical Sciences, Ghent University, Gent, Belgium
| | - Philippe Lefebvre
- Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011-EGID, Lille, France
| | - Bart Staels
- Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011-EGID, Lille, France
| | - Jerome Eeckhoute
- Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011-EGID, Lille, France
| |
Collapse
|
43
|
Fan W, Bradford TM, Török NJ. Metabolic dysfunction-associated liver disease and diabetes: Matrix remodeling, fibrosis, and therapeutic implications. Ann N Y Acad Sci 2024; 1538:21-33. [PMID: 38996214 DOI: 10.1111/nyas.15184] [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] [Indexed: 07/14/2024]
Abstract
Metabolic dysfunction-associated liver disease (MASLD) and steatohepatitis (MASH) are becoming the most common causes of chronic liver disease in the United States and worldwide due to the obesity and diabetes epidemics. It is estimated that by 2030 close to 100 million people might be affected and patients with type 2 diabetes are especially at high risk. Twenty to 30% of patients with MASLD can progress to MASH, which is characterized by steatosis, necroinflammation, hepatocyte ballooning, and in advanced cases, fibrosis progressing to cirrhosis. Clinically, it is recognized that disease progression in diabetic patients is accelerated and the role of various genetic and epigenetic factors, as well as cell-matrix interactions in fibrosis and stromal remodeling, have recently been recognized. While there has been great progress in drug development and clinical trials for MASLD/MASH, the complexity of these pathways highlights the need to improve diagnosis/early detection and develop more successful antifibrotic therapies that not only prevent but reverse fibrosis.
Collapse
Affiliation(s)
- Weiguo Fan
- Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Stanford, California, USA
- Palo Alto VA Medical Center, Palo Alto, California, USA
| | - Toby M Bradford
- Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Stanford, California, USA
| | - Natalie J Török
- Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Stanford, California, USA
- Palo Alto VA Medical Center, Palo Alto, California, USA
| |
Collapse
|
44
|
Sonkar R, Ma H, Waxman DJ. Steatotic liver disease induced by TCPOBOP-activated hepatic constitutive androstane receptor: primary and secondary gene responses with links to disease progression. Toxicol Sci 2024; 200:324-345. [PMID: 38710495 PMCID: PMC11285164 DOI: 10.1093/toxsci/kfae057] [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] [Indexed: 05/08/2024] Open
Abstract
Constitutive androstane receptor (CAR, Nr1i3), a liver nuclear receptor and xenobiotic sensor, induces drug, steroid, and lipid metabolizing enzymes, stimulates liver hypertrophy and hyperplasia, and ultimately, hepatocellular carcinogenesis. The mechanisms linking early CAR responses to later disease development are poorly understood. Here we show that exposure of CD-1 mice to TCPOBOP (1,4-bis[2-(3,5-dichloropyridyloxy)]benzene), a halogenated xenochemical and selective CAR agonist ligand, induces pericentral steatosis marked by hepatic accumulation of cholesterol and neutral lipid, and elevated circulating alanine aminotransferase, indicating hepatocyte damage. TCPOBOP-induced steatosis was weaker in the pericentral region but stronger in the periportal region in females compared with males. Early (1 day) TCPOBOP transcriptional responses were enriched for CAR-bound primary response genes, and for lipogenesis and xenobiotic metabolism and oxidative stress protection pathways; late (2 weeks) TCPOBOP responses included many CAR binding-independent secondary response genes, with enrichment for macrophage activation, immune response, and cytokine and reactive oxygen species production. Late upstream regulators specific to TCPOBOP-exposed male liver were linked to proinflammatory responses and hepatocellular carcinoma progression. TCPOBOP administered weekly to male mice using a high corn oil vehicle induced carbohydrate-responsive transcription factor (MLXIPL)-regulated target genes, dysregulated mitochondrial respiratory and translation regulatory pathways, and induced more advanced liver pathology. Overall, TCPOBOP exposure recapitulates histological and gene expression changes characteristic of emerging steatotic liver disease, including secondary gene responses in liver nonparenchymal cells indicative of transition to a more advanced disease state. Upstream regulators of both the early and late TCPOBOP response genes include novel biomarkers for foreign chemical-induced metabolic dysfunction-associated steatotic liver disease.
Collapse
Affiliation(s)
- Ravi Sonkar
- Department of Biology and Bioinformatics Program, Boston University, Boston, Massachusetts 02215, USA
| | - Hong Ma
- Department of Biology and Bioinformatics Program, Boston University, Boston, Massachusetts 02215, USA
| | - David J Waxman
- Department of Biology and Bioinformatics Program, Boston University, Boston, Massachusetts 02215, USA
| |
Collapse
|
45
|
Dai R, Sun M, Lu M, Deng L. Deep learning for predicting fibrotic progression risk in diabetic individuals with metabolic dysfunction-associated steatotic liver disease initially free of hepatic fibrosis. Heliyon 2024; 10:e34150. [PMID: 39071617 PMCID: PMC11282990 DOI: 10.1016/j.heliyon.2024.e34150] [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: 05/07/2024] [Revised: 07/04/2024] [Accepted: 07/04/2024] [Indexed: 07/30/2024] Open
Abstract
Objective Metabolic dysfunction-associated steatotic liver disease (MASLD) significantly impacts patients with type 2 diabetes mellitus (T2DM), where current non-invasive assessment methods show limited predictive power for future fibrotic progression. This study aims to develop an enhanced deep learning (DL) model that integrates ultrasound elastography images with clinical data, refining the prediction of fibrotic progression in T2DM patients with MASLD who initially exhibit no signs of hepatic fibrosis. Methods We enrolled 946 diabetic MASLD patients without advanced fibrosis, confirmed by initial liver stiffness measurements (LSM) below 6.5 kPa. Patients were divided into a training dataset of 671 and a testing dataset of 275. Hepatic shear wave elastography (SWE) images measured liver stiffness, classifying participants based on progression. A DL integrated model (DI-model) combining SWE images and clinical data was trained and its predictive performance compared with individual Image and Tabular models, as well as a logistic regression model on the testing dataset. Results Fibrotic progression was observed in 18.1 % of patients over three years. During the training phase, the DI-model outperformed other models, achieving the lowest validation loss of 0.161 and highest accuracy of 0.933 through cross-validation. In the testing phase, it demonstrated robust discrimination with AUCs of 0.884 and 0.903 for the receiver operating characteristic and precision-recall curves, respectively, clearly outperforming other models. Shapley analysis identified BMI, LSM, and glycated hemoglobin as critical predictors. Conclusion The DI-model significantly enhances the prediction of future fibrotic progression in diabetic MASLD patients, demonstrating the benefit of combining clinical and imaging data for early diagnosis and intervention.
Collapse
Affiliation(s)
- Ruihong Dai
- Department of Ultrasound, Meng Cheng County Hospital of Chinese Medicine, Bozhou City, Anhui Province, China
| | - Miaomiao Sun
- Department of Ultrasound, Meng Cheng County Hospital of Chinese Medicine, Bozhou City, Anhui Province, China
| | - Mei Lu
- Department of Ultrasound, Meng Cheng County Hospital of Chinese Medicine, Bozhou City, Anhui Province, China
| | - Lanhua Deng
- Department of Ultrasound, Meng Cheng County Hospital of Chinese Medicine, Bozhou City, Anhui Province, China
| |
Collapse
|
46
|
Kim HY, Lee W, Liu X, Jang H, Sakane S, Carvalho-Gontijo Weber R, Diggle K, Kerk SA, Metallo CM, Kisseleva T, Brenner DA. Protocol to generate human liver spheroids to study liver fibrosis induced by metabolic stress. STAR Protoc 2024; 5:103111. [PMID: 38833372 PMCID: PMC11179098 DOI: 10.1016/j.xpro.2024.103111] [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: 04/01/2024] [Revised: 05/05/2024] [Accepted: 05/15/2024] [Indexed: 06/06/2024] Open
Abstract
Currently, there is no effective treatment for obesity and alcohol-associated liver diseases, partially due to the lack of translational human models. Here, we present a protocol to generate 3D human liver spheroids that contain all the liver cell types and mimic "livers in a dish." We describe strategies to induce metabolic and alcohol-associated hepatic steatosis, inflammation, and fibrosis. We outline potential applications, including using human liver spheroids for experimental and translational research and drug screening to identify potential anti-fibrotic therapies.
Collapse
Affiliation(s)
- Hyun Young Kim
- Department of Medicine, University of California, San Diego, School of Medicine, La Jolla, CA 92093, USA
| | - Wonseok Lee
- Department of Medicine, University of California, San Diego, School of Medicine, La Jolla, CA 92093, USA
| | - Xiao Liu
- Department of Medicine, University of California, San Diego, School of Medicine, La Jolla, CA 92093, USA; Department of Surgery, University of California, San Diego, School of Medicine, La Jolla, CA 92093, USA
| | - Haeum Jang
- Department of Medicine, University of California, San Diego, School of Medicine, La Jolla, CA 92093, USA
| | - Sadatsugu Sakane
- Department of Medicine, University of California, San Diego, School of Medicine, La Jolla, CA 92093, USA
| | | | - Karin Diggle
- Department of Medicine, University of California, San Diego, School of Medicine, La Jolla, CA 92093, USA; Department of Surgery, University of California, San Diego, School of Medicine, La Jolla, CA 92093, USA
| | - Samuel A Kerk
- Molecular and Cell Biology Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037, USA
| | - Christian M Metallo
- Molecular and Cell Biology Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037, USA
| | - Tatiana Kisseleva
- Department of Surgery, University of California, San Diego, School of Medicine, La Jolla, CA 92093, USA.
| | - David A Brenner
- Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA.
| |
Collapse
|
47
|
Ramos-Molina B, Rossell J, Pérez-Montes de Oca A, Pardina E, Genua I, Rojo-López MI, Julián MT, Alonso N, Julve J, Mauricio D. Therapeutic implications for sphingolipid metabolism in metabolic dysfunction-associated steatohepatitis. Front Endocrinol (Lausanne) 2024; 15:1400961. [PMID: 38962680 PMCID: PMC11220194 DOI: 10.3389/fendo.2024.1400961] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/14/2024] [Accepted: 06/03/2024] [Indexed: 07/05/2024] Open
Abstract
The prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD), a leading cause of chronic liver disease, has increased worldwide along with the epidemics of obesity and related dysmetabolic conditions characterized by impaired glucose metabolism and insulin signaling, such as type 2 diabetes mellitus (T2D). MASLD can be defined as an excessive accumulation of lipid droplets in hepatocytes that occurs when the hepatic lipid metabolism is totally surpassed. This metabolic lipid inflexibility constitutes a central node in the pathogenesis of MASLD and is frequently linked to the overproduction of lipotoxic species, increased cellular stress, and mitochondrial dysfunction. A compelling body of evidence suggests that the accumulation of lipid species derived from sphingolipid metabolism, such as ceramides, contributes significantly to the structural and functional tissue damage observed in more severe grades of MASLD by triggering inflammatory and fibrogenic mechanisms. In this context, MASLD can further progress to metabolic dysfunction-associated steatohepatitis (MASH), which represents the advanced form of MASLD, and hepatic fibrosis. In this review, we discuss the role of sphingolipid species as drivers of MASH and the mechanisms involved in the disease. In addition, given the absence of approved therapies and the limited options for treating MASH, we discuss the feasibility of therapeutic strategies to protect against MASH and other severe manifestations by modulating sphingolipid metabolism.
Collapse
Affiliation(s)
- Bruno Ramos-Molina
- Group of Obesity, Diabetes & Metabolism, Instituto Murciano de Investigación Biosanitaria (IMIB), Murcia, Spain
| | - Joana Rossell
- Group of Endocrinology, Diabetes & Nutrition, Institut de Recerca SANT PAU, Barcelona, Spain
- Centro de Investigación Biomédica en Red (CIBER) de Diabetes y Enfermedades Metabólicas Asociadas, Instituto de Salud Carlos III, Madrid, Spain
| | | | - Eva Pardina
- Department de Biochemistry & Molecular Biology, Facultat de Biologia, Universitat de Barcelona (UB), Barcelona, Spain
| | - Idoia Genua
- Department of Endocrinology & Nutrition, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
| | - Marina I. Rojo-López
- Group of Endocrinology, Diabetes & Nutrition, Institut de Recerca SANT PAU, Barcelona, Spain
| | - María Teresa Julián
- Department of Endocrinology & Nutrition, Hospital Universitari Germans Trias i Pujol, Badalona, Spain
| | - Núria Alonso
- Centro de Investigación Biomédica en Red (CIBER) de Diabetes y Enfermedades Metabólicas Asociadas, Instituto de Salud Carlos III, Madrid, Spain
- Department of Endocrinology & Nutrition, Hospital Universitari Germans Trias i Pujol, Badalona, Spain
| | - Josep Julve
- Group of Endocrinology, Diabetes & Nutrition, Institut de Recerca SANT PAU, Barcelona, Spain
- Centro de Investigación Biomédica en Red (CIBER) de Diabetes y Enfermedades Metabólicas Asociadas, Instituto de Salud Carlos III, Madrid, Spain
| | - Didac Mauricio
- Group of Endocrinology, Diabetes & Nutrition, Institut de Recerca SANT PAU, Barcelona, Spain
- Centro de Investigación Biomédica en Red (CIBER) de Diabetes y Enfermedades Metabólicas Asociadas, Instituto de Salud Carlos III, Madrid, Spain
- Department of Endocrinology & Nutrition, Hospital Universitari Germans Trias i Pujol, Badalona, Spain
- Department of Endocrinology & Nutrition, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
- Faculty of Medicine, University of Vic/Central University of Catalonia (UVIC/UCC), Vic, Spain
| |
Collapse
|
48
|
Okumura A, Aoshima K, Tanimizu N. Generation of in vivo-like multicellular liver organoids by mimicking developmental processes: A review. Regen Ther 2024; 26:219-234. [PMID: 38903867 PMCID: PMC11186971 DOI: 10.1016/j.reth.2024.05.020] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2024] [Revised: 05/24/2024] [Accepted: 05/30/2024] [Indexed: 06/22/2024] Open
Abstract
Liver is involved in metabolic reactions, ammonia detoxification, and immunity. Multicellular liver tissue cultures are more desirable for drug screening, disease modeling, and researching transplantation therapy, than hepatocytes monocultures. Hepatocytes monocultures are not stable for long. Further, hepatocyte-like cells induced from pluripotent stem cells and in vivo hepatocytes are functionally dissimilar. Organoid technology circumvents these issues by generating functional ex vivo liver tissue from intrinsic liver progenitor cells and extrinsic stem cells, including pluripotent stem cells. To function as in vivo liver tissue, the liver organoid cells must be arranged precisely in the 3-dimensional space, closely mimicking in vivo liver tissue. Moreover, for long term functioning, liver organoids must be appropriately vascularized and in contact with neighboring epithelial tissues (e.g., bile canaliculi and intrahepatic bile duct, or intrahepatic and extrahepatic bile ducts). Recent discoveries in liver developmental biology allows one to successfully induce liver component cells and generate organoids. Thus, here, in this review, we summarize the current state of knowledge on liver development with a focus on its application in generating different liver organoids. We also cover the future prospects in creating (functionally and structurally) in vivo-like liver organoids using the current knowledge on liver development.
Collapse
Affiliation(s)
- Ayumu Okumura
- Division of Regenerative Medicine, Center for Stem Cell Biology and Regenerative Medicine, The Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-0071, Japan
| | - Kenji Aoshima
- Division of Regenerative Medicine, Center for Stem Cell Biology and Regenerative Medicine, The Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-0071, Japan
| | - Naoki Tanimizu
- Division of Regenerative Medicine, Center for Stem Cell Biology and Regenerative Medicine, The Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-0071, Japan
| |
Collapse
|
49
|
Lonardo A. PRO-C3, liver fibrosis and CKD: The plot thickens. Liver Int 2024; 44:1126-1128. [PMID: 38634694 DOI: 10.1111/liv.15888] [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: 02/14/2024] [Revised: 02/16/2024] [Accepted: 02/19/2024] [Indexed: 04/19/2024]
Affiliation(s)
- Amedeo Lonardo
- Department of Internal Medicine, Azienda Ospedaliero-Universitaria di Modena (-2023), Modena, Italy
| |
Collapse
|
50
|
Muturi HT, Ghadieh HE, Asalla S, Lester SG, Verhulst S, Stankus HL, Zaidi S, Abdolahipour R, Belew GD, van Grunsven LA, Friedman SL, Schwabe RF, Hinds TD, Najjar SM. Conditional deletion of CEACAM1 causes hepatic stellate cell activation. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.04.02.586238. [PMID: 38617330 PMCID: PMC11014538 DOI: 10.1101/2024.04.02.586238] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/16/2024]
Abstract
Objectives Hepatic CEACAM1 expression declines with advanced hepatic fibrosis stage in patients with MASH. Global and hepatocyte-specific deletions of Ceacam1 impair insulin clearance to cause hepatic insulin resistance and steatosis. They also cause hepatic inflammation and fibrosis, a condition characterized by excessive collagen production from activated hepatic stellate cells (HSCs). Given the positive effect of PPARγ on CEACAM1 transcriptoin and on HSCs quiescence, the current studies investigated whether CEACAM1 loss from HSCs causes their activation. Methods We examined whether lentiviral shRNA-mediated CEACAM1 donwregulation (KD-LX2) activates cultured human LX2 stellate cells. We also generated LratCre+Cc1 fl/fl mutants with conditional Ceacam1 deletion in HSCs and characterized their MASH phenotype. Media transfer experiments were employed to examine whether media from mutant human and murine HSCs activate their wild-type counterparts. Results LratCre+Cc1 fl/fl mutants displayed hepatic inflammation and fibrosis but without insulin resistance or hepatic steatosis. Their HSCs, like KD-LX2 cells, underwent myofibroblastic transformation and their media activated wild-type HDCs. This was inhibited by nicotinic acid treatment which stemmed the release of IL-6 and fatty acids, both of which activate the epidermal growth factor receptor (EGFR) tyrosine kinase. Gefitinib inhibition of EGFR and its downstream NF-κB/IL-6/STAT3 inflammatory and MAPK-proliferation pathways also blunted HSCs activation in the absence of CEACAM1. Conclusions Loss of CEACAM1 in HSCs provoked their myofibroblastic transformation in the absence of insulin resistance and hepatic steatosis. This response is mediated by autocrine HSCs activation of the EGFR pathway that amplifies inflammation and proliferation.
Collapse
|