Liver fibrosis in NAFLD/NASH: from pathophysiology towards diagnostic and therapeutic strategies

Molecular Aspects of Medicine, Journal Year: 2023, Volume and Issue: 95, P. 101231 - 101231

Published: Dec. 5, 2023

Liver fibrosis, as an excess deposition of extracellular matrix (ECM) components, results from chronic liver injury well persistent activation inflammatory response and fibrogenesis. fibrosis is a major determinant for disease (CLD) progression in the last two decades our understanding on molecular cellular mechanisms underlying fibrogenic CLD has dramatically improved, boosting pre-clinical studies clinical trials designed to find novel therapeutic approaches. From these several critical concepts have emerged, starting reveal complexity pro-fibrotic microenvironment which involves very complex, dynamic interrelated interactions between different hepatic extrahepatic cell populations. This review will offer first recapitulation established pathophysiological basic principles by intentionally focus attention NAFLD/NASH, metabolic-related form with high impact general population emerging leading cause worldwide. NAFLD/NASH-related pro-inflammatory profibrogenic be analysed information cells, mediators signalling pathways taken advantage methodological approaches techniques (single genomics, imaging mass cytometry, vitro two- three-dimensional models, etc.). We next overview recent advancement diagnostic prognostic tools, including serum biomarkers polygenic scores, support analysis biopsies. Finally, this provide current therapies treatment NAFLD/NASH patients.

Language: Английский

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Friend or foe? The elusive role of hepatic stellate cells in liver cancer

Nature Reviews Gastroenterology & Hepatology, Journal Year: 2023, Volume and Issue: 20(10), P. 647 - 661

Published: Aug. 7, 2023

Language: Английский

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Found in translation—Fibrosis in metabolic dysfunction–associated steatohepatitis (MASH)

Science Translational Medicine, Journal Year: 2023, Volume and Issue: 15(716)

Published: Oct. 4, 2023

Metabolic dysfunction–associated steatohepatitis (MASH) is a severe form of liver disease that poses global health threat because its potential to progress advanced fibrosis, leading cirrhosis and cancer. Recent advances in single-cell methodologies, refined models, genetic epigenetic insights have provided nuanced understanding MASH fibrogenesis, with substantial cellular heterogeneity livers providing potentially targetable cell-cell interactions behavior. Unlike mechanisms underlying fibrosis regression are still inadequately understood, although antifibrotic targets been recently identified. A treatment framework could lead noninvasive assessment targeted therapies preserve hepatocellular function restore the liver’s architectural integrity.

Language: Английский

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MAIT cell inhibition promotes liver fibrosis regression via macrophage phenotype reprogramming

Nature Communications, Journal Year: 2023, Volume and Issue: 14(1)

Published: April 1, 2023

Recent data have shown that liver fibrosis can regress even at later stages of cirrhosis and shifting the immune response from pro-inflammatory towards a resolutive profile is considered as promising option. The regulatory networks govern shift inflammatory phenotype thus potential reversal are lesser known. Here we show in precision-cut human slices obtained patients with end-stage mouse models, inhibiting Mucosal-Associated Invariant T (MAIT) cells using pharmacological or antibody-driven approaches, limits progression regresses fibrosis, following chronic toxic- non-alcoholic steatohepatitis (NASH)-induced injury. Mechanistic studies, combining RNA sequencing, vivo functional studies (performed male mice) co-culture experiments indicate disruption MAIT cell-monocyte/macrophage interaction results resolution both by increasing frequency restorative Ly6Clo expenses pro-fibrogenic Ly6Chi monocyte-derived macrophages promoting an autophagic subsets. Thus, our cell activation consequential important pathogenic features could be targeted anti-fibrogenic therapy.

Language: Английский

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Hepatic Stellate Cells: Dictating Outcome in Nonalcoholic Fatty Liver Disease

Cellular and Molecular Gastroenterology and Hepatology, Journal Year: 2023, Volume and Issue: 15(6), P. 1277 - 1292

Published: Jan. 1, 2023

Nonalcoholic fatty liver disease (NAFLD) is a fast growing, chronic affecting ∼25% of the global population. severity ranges from less severe simple hepatic steatosis to more advanced nonalcoholic steatohepatitis (NASH). The presence NASH predisposes individuals fibrosis, which can further progress cirrhosis and hepatocellular carcinoma. This makes fibrosis an important indicator clinical outcomes in patients with NASH. Hepatic stellate cell activation dictates development during Here, we discuss recent advances analysis profibrogenic pathways mediators inactivation, ultimately determine course disease/NASH. SummaryNonalcoholic frequently progresses outcomes. As NAFLD, that mediate inactivation NAFLD. most prevalent worldwide prevalence rates around 25% nearly 30% adult population, continue increase.1Younossi Z.M. Koenig A.B. Abdelatif D. et al.Global epidemiology disease: meta-analytic assessment prevalence, incidence, outcomes.Hepatology. 2016; 64: 73-84Crossref PubMed Scopus (5731) Google Scholar,2Le M.H. Yeo Y.H. Li X. NAFLD prevalence: systematic review meta-analysis.Clin Gastroenterol Hepatol. 2019; 2022: 2809-2817Google Scholar Because targeted therapies are still lacking, represents high burden for those affected health care systems world.3Sanyal A.J. Van Natta M.L. Clark J. al.Prospective study adults disease.N Engl J Med. 2021; 385: 1559-1569Crossref (189) Scholar,4Younossi Blissett R. al.The economic United States Europe.Hepatology. 1577-1586Crossref (716) considered manifestation metabolic syndrome closely associated diabetes mellitus, obesity, dyslipidemia.5Diehl A.M. Day C. Cause, pathogenesis, treatment steatohepatitis.N 2017; 377: 2063-2072Crossref (678) encompasses several pathologies ranging lipid accumulation (hepatic steatosis) (NASH).6Musso G. Cassader M. Gambino Non-alcoholic steatohepatitis: emerging molecular targets therapeutic strategies.Nat Rev Drug Discov. 15: 249-274Crossref (301) characterized by cellular stress, hepatocyte death, inflammation, may cirrhosis, carcinoma.7Liu W. Baker R.D. Bhatia T. al.Pathogenesis steatohepatitis.Cell Mol Life Sci. 73: 1969-1987Crossref (133) transition crucial because key determinant adverse mortality liver-related complications increase higher stages.3Sanyal Scholar,8Angulo P. Kleiner D.E. Dam-Larsen S. al.Liver but no other histologic features, long-term disease.Gastroenterology. 2015; 149: 389-397Abstract Full Text PDF (1768) impact as demonstrated fact fastest growing cause carcinoma listed transplantation States.9Younossi Z. Stepanova Ong J.P. al.Nonalcoholic transplant candidates.Clin 17: 748-755Abstract (433) A mechanism driving cells; once activated they differentiate into highly proliferative, extracellular matrix–producing myofibroblasts.10Schwabe R.F. Tabas I. Pajvani U.B. Mechanisms steatohepatitis.Gastroenterology. 2020; 158: 1913-1928Abstract Therefore, understanding underlying mechanisms fundamental developing effective NAFLD/NASH. provides overview pathologic functions cells context discusses involved their deactivation, approaches targeting these mechanisms. umbrella term encompassing various including or NASH.11Friedman S.L. Neuschwander-Tetri B.A. Rinella al.Mechanisms 2018; 24: 908-922Crossref (1634) pathogenesis multifactorial, resulting numerous conditions acting parallel, such abnormal metabolism, genetic predisposition, lipotoxicity, oxidative gut dysbiosis, endoplasmic reticulum mitochondrial dysfunction, inflammation.11Friedman Scholar,12Caligiuri A. Gentilini Marra F. Molecular NASH.Int 1575Crossref (0) obesity dysregulation, adipose tissue exhibits low-grade inflammation secretes adipokines inflammatory cytokines, leptin, tumor necrosis factor (TNF), interleukin (IL)6.13Nati Chung K.J. Chavakis role innate immune disease.J Innate Immun. 2022; 14: 31-41Crossref (14) Furthermore, correlates insulin resistance, reactive oxygen species generation.13Nati Scholar,14Chakravarthy M.V. basis steatohepatitis.Endocrinol Diabetes Metab. 3e00112Crossref (36) Additionally, microbiota dysbiosis dysfunctional barrier increased gut-derived bacterial products, lipopolysaccharides liver.13Nati Scholar,15Aron-Wisnewsky Vigliotti Witjes al.Gut human NAFLD: disentangling microbial signatures disorders.Nat 279-297Crossref (354) During intrahepatic extrahepatic triggers lead liver-resident recruitment additional adaptive systems.16Cai Zhang X.J. H. steatohepatitis.Hepatology. 70: 1026-1037Crossref (108) Scholar,17Sutti Albano E. Adaptive immunity: player progression NAFLD.Nat 81-92Crossref (150) In particular, resident macrophages named Kupffer play major promoting NAFLD.18Kazankov K. Jorgensen S.M.D. Thomsen K.L. steatohepatitis.Nat 16: 145-159Crossref (394) leads secretion proinflammatory chemokines chemokine (C-C motif) ligand 2 (CCL2), CCL3, CCL5, TNF-α, IL1β, IL6, aggravates recruiting cells, monocyte-derived macrophages, neutrophils, lymphocytes.19Krenkel O. Tacke Macrophages model pathogenic immunometabolism.Semin Liver Dis. 37: 189-197Crossref (6) Scholar, 20Heinrichs Berres Nellen CCL3 promotes experimental mice.PLoS One. 2013; 8e66106Crossref (43) 21Berres Koenen R.R. Rueland al.Antagonism Ccl5 ameliorates mice.J Clin Invest. 2010; 120: 4129-4140Crossref (198) Although tend be mostly asymptomatic respect at earlier stages incidence symptoms increases line findings histopathologic alone not reliable predictor progression.22Hagstrom Nasr Ekstedt al.Fibrosis stage predicts time biopsy-proven NAFLD.J 67: 1265-1273Abstract (549) Fibrosis critical NASH, risk death F3 F4 fibrosis.3Sanyal Scholar,23Vilar-Gomez Calzadilla-Bertot L. Wai-Sun Wong V. cause-specific multi-national cohort study.Gastroenterology. 155: 443-457Abstract (412) nonparenchymal represent main fibrogenic type account approximately 5%–8% all normal liver.24Geerts History, heterogeneity, developmental biology, quiescent cells.Semin 2001; 21: 311-335Crossref (611) Scholar,25Mederacke Hsu C.C. Troeger J.S. al.Fate tracing reveals dominant contributors independent its aetiology.Nat Commun. 4: 2823Crossref (852) localized space Disse, between basolateral region hepatocytes antiluminal surface sinusoidal endothelial cells.26Friedman cells: protean, multifunctional, enigmatic liver.Physiol Rev. 2008; 88: 125-172Crossref (2102) healthy liver, resting, have cytoplasmic processes aid making contact surrounding hepatocytes, assist intercellular transport cytokines soluble mediators.26Friedman distinct feature storage retinoids (vitamin metabolites) within droplets.26Friedman Scholar,27Sufletel R.T. Melincovici C.S. Gheban al.Hepatic - past till present: morphology, markers, lines, behavior pathology.Rom Morphol Embryol. 61: 615-642Crossref Under conditions, 80%–90% stored droplets There extensive crosstalk macrophages.28Chang Hisamatsu Shimamura al.Activated differentiation macrophages.Hepatol Res. 43: 658-669Crossref (40) Scholar,29Xiong Kuang Ansari al.Landscape revealed single-cell secretome gene analysis.Mol Cell. 75: 644-660Abstract (306) vitro experiments using show molecules derived induce phenotype.28Chang RNA sequencing data suggest communicate secreting variety factors "stellakines," many upregulated injury. Thus, enhanced stellakines linked pathogenesis.29Xiong stimuli injury (Figure 1).30Trivedi Wang Friedman power plasticity-metabolic regulation cells.Cell 33: 242-257Abstract (87) produce myofibroblasts injury, shown rodent models NASH.25Mederacke Scholar,31Friedman Roll F.J. Boyles lipocytes: principal collagen-producing rat liver.Proc Natl Acad Sci U S 1985; 82: 8681-8685Crossref transdifferentiation myofibroblasts, marked changes expression profile.10Schwabe Scholar,32Wang Z.Y. Keogh Waldt al.Single-cell bulk transcriptomics potential fibrosis.Sci Rep. 1119396Google These exhibit contractile, phenotype, distinguished loss retinol-containing droplets.33Tsuchida activation.Nat 397-411Crossref (1355) useful acute sustained seen results excess matrix fibrosis.10Schwabe Activated secrete wide range CCL2, IL8, (C-X-C ligand-12 (CXCL12), express adhesion molecules, molecule 1 vascular receptors (CCR5), infiltration liver.34Carter J.K. cell-immune interactions NASH.Front Endocrinol (Lausanne). 13867940Crossref (3) rather homogeneous, cells/myofibroblasts much heterogeneous.29Xiong Scholar,35Krenkel Hundertmark Ritz T.P. al.Single identifies subsets fibrosis.Cells. 8: 503Crossref Single-cell studies performed mouse livers identified resting fibrotic cirrhotic livers.35Krenkel 36Dobie Wilson-Kanamori J.R. Henderson B.E.P. uncovers zonation function mesenchyme fibrosis.Cell 29: 1832-1847Abstract (149) 37Rosenthal S.B. Liu Ganguly al.Heterogeneity HSCs NASH.Hepatology. 74: 667-685Crossref (33) 38Ramachandran Dobie al.Resolving niche level.Nature. 575: 512-518Crossref 39Filliol Saito Y. Nair al.Opposing roles subpopulations hepatocarcinogenesis.Nature. 610: 356-3565Crossref (15) Functionally, levels growth protect whereas mainly proteins, different types collagen I, also III, VI, XIV, chemokines, fibrogenesis.29Xiong Scholar,39Filliol immunoregulatory effects: apoptosis T via programmed 1; influence B-cell activity same mice; exert positive on tolerancing immune, FoxP3+ regulatory myeloid-derived suppressor models.40Charles Chou H.S. al.Human inhibit T-cell response through B7-H1 pathway.Transplantation. 96: 17-24Crossref 41Li Lu Qian directly b death-ligand 1.J Immunol. 196: 1617-1625Crossref (17) 42Jiang Yang H.R. preferentially expand allogeneic CD4+ CD25+ IL-2-dependent manner.Transplantation. 86: 1492-1502Crossref (82) 43Chou Hsieh regulate way induction myeloid mice.Hepatology. 2011; 53: 1007-1019Crossref (101) Currently, it yet clear under tolerogenic. Several trigger diverse cells.33Tsuchida described detail later sections. mediated factors, transforming (TGF)β, platelet-derived (PDGF), epidermal (EGF) 1). TGFβ potent activator driver fibrogenesis.10Schwabe Of note, elevated serum NAFLD.44Sepulveda-Flores R.N. Vera-Cabrera Flores-Gutierrez al.Obesity-related non-alcoholic TGF-beta1 relation morbid obesity.Ann 2002; 1: 36-39Crossref Scholar,45Tarantino Conca Riccio al.Enhanced concentrations factor-beta1 liver: really benign?.J Transl 6: 72Crossref originates feed-forward loop.46Dewidar B. Meyer Dooley al.TGF-beta fibrogenesis-updated 2019.Cells. 1419Crossref (288) producing TGFβ.10Schwabe When occurs, recruited apoptotic process efferocytosis, induces production leading cells.10Schwabe Scholar,47Kourtzelis Hajishengallis Phagocytosis resolution inflammation.Front 11: 553Crossref (99) Accordingly, inhibition pathway reduced attenuates effect was pronounced when IL13 inhibited simultaneously.48Hart K.M. Fabre Sciurba J.C. al.Type immunity protective exacerbates collaboratively TGF-beta.Sci 9eaal3694Crossref (80) Mechanistically, TGFβ-induced phosphorylation SMAD 3, upregulation I III synthesis complexes phosphorylated transcription factors.49Furukawa Matsuzaki Mori al.p38 MAPK mediates signal Smad3 myofibroblasts.Hepatology. 2003; 38: 879-889Crossref 50Yoshida al.Transforming factor-beta c-Jun N-terminal kinase-dependent Smad2/3 after injury.Am Pathol. 2005; 166: 1029-1039Abstract 51Breitkopf Godoy Ciuclan al.TGF-beta/Smad signaling injured liver.Z Gastroenterol. 2006; 44: 57-66Crossref (156) Genes include α-smooth muscle actin (α-SMA) connective (CTGF).46Dewidar SMAD-independent manner mitogen-activated protein kinase-1, p38, kinase mechanisms, among others.52Engel M.E. McDonnell M.A. Law B.K. al.Interdependent JNK factor-beta-mediated transcription.J Biol Chem. 1999; 274: 37413-37420Abstract (441) Scholar,53Hanafusa Ninomiya-Tsuji Masuyama N. al.Involvement p38 factor-beta-induced expression.J 27161-27167Abstract (384) addition direct effects, latent deposited become subsequently contraction integrin-αV mechanisms.54Wipff P.J. Rifkin D.B. Meister J.J. al.Myofibroblast activates matrix.J Cell Biol. 2007; 179: 1311-1323Crossref (992) Scholar,55Annes Chen Munger al.Integrin alphaVbeta6-mediated TGF-beta requires binding protein-1.J 2004; 165: 723-734Crossref (385) Concordantly, has antifibrotic effects injury.54Wipff epigenetic regulator TET3 TGFβ/SMAD2/3 pathway, microRNA-488-5p mice induced CCl4 treatment, high-fat diet, bile duct ligation.56Qiu Wu al.miR-488-5p mitigates suppressing expression.Hepatol Int. Crossref

Language: Английский

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Role of hepatic peroxisome proliferator-activated receptor γ in non-alcoholic fatty liver disease

Journal of Endocrinology, Journal Year: 2023, Volume and Issue: 257(1)

Published: Jan. 23, 2023

Peroxisome proliferator-activated receptor γ (PPARγ) belongs to a family of nuclear receptors that could serve as lipid sensors. PPARγ is the target group insulin sensitizers called thiazolidinediones (TZDs) which regulate expression genes involved in glucose and metabolism well adipokines metabolic function other tissues. Non-alcoholic fatty liver disease (NAFLD) has high prevalence worldwide even higher patients with obesity resistance. TZD-mediated activation good treatment for NAFLD because TZDs have shown anti-fibrogenic anti-inflammatory effects vitro increase sensitivity peripheral tissues improves pathology. However, mechanistic studies mouse models suggest hepatocytes might reduce or limit therapeutic potential TZD against NAFLD. In this review, we briefly describe short history PPAR isoforms, relevance their different tissues, pathogenesis therapeutics We also discuss some evidence derived from be useful endocrinologists assess tissue-specific roles PPARs, complement reverse endocrinology approaches, understand direct role non-parenchymal cells.

Language: Английский

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Maternal diet alters long-term innate immune cell memory in fetal and juvenile hematopoietic stem and progenitor cells in nonhuman primate offspring

Cell Reports, Journal Year: 2023, Volume and Issue: 42(4), P. 112393 - 112393

Published: April 1, 2023

Maternal overnutrition increases inflammatory and metabolic disease risk in postnatal offspring. This constitutes a major public health concern due to increasing prevalence of these diseases, yet mechanisms remain unclear. Here, using nonhuman primate models, we show that maternal Western-style diet (mWSD) exposure is associated with persistent pro-inflammatory phenotypes at the transcriptional, metabolic, functional levels bone marrow-derived macrophages (BMDMs) from 3-year-old juvenile offspring hematopoietic stem progenitor cells (HSPCs) fetal marrow liver. mWSD also increased oleic acid Assay for transposase-accessible chromatin sequencing (ATAC-seq) profiling HSPCs BMDMs mWSD-exposed juveniles supports model which transmit memory myeloid beginning utero. These findings alters long-term immune cell developmental programming proposed consequences chronic diseases featuring altered immune/inflammatory activation across lifespan.

Language: Английский

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Inflammatory signaling in NASH driven by hepatocyte mitochondrial dysfunctions

Journal of Translational Medicine, Journal Year: 2023, Volume and Issue: 21(1)

Published: Oct. 26, 2023

Abstract Liver steatosis, inflammation, and variable degrees of fibrosis are the pathological manifestations nonalcoholic steatohepatitis (NASH), an aggressive presentation most prevalent chronic liver disease in Western world known as fatty (NAFL). Mitochondrial hepatocyte dysfunction is a primary event that triggers affecting Kupffer hepatic stellate cell behaviour. Here, we consider role impaired mitochondrial function caused by lipotoxicity during oxidative stress hepatocytes. Dysfunction phosphorylation ROS production cause release damage-associated molecular patterns from dying hepatocytes, leading to activation innate immunity trans-differentiation cells, thereby driving NASH.

Language: Английский

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Hepatic Fibrosis and Cancer: The Silent Threats of Metabolic Syndrome

Diabetes & Metabolism Journal, Journal Year: 2024, Volume and Issue: 48(2), P. 161 - 169

Published: Jan. 26, 2024

Metabolic dysfunction-associated steatotic (fatty) liver disease (MASLD), previously termed non-alcoholic fatty disease, is a worldwide epidemic that can lead to hepatic inflammation, fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). The typically component of the metabolic syndrome accompanies obesity, often overlooked because manifestations are clinically silent until late-stage present (i.e., cirrhosis). Moreover, Asian populations, including Koreans, have higher fraction patients who lean, yet their illness has same prognosis or worse than those obese. Nonetheless, ongoing injury inflammation ballooning hepatocytes as classic features. Over time, fibrosis develops following activation stellate cells, liver’s main fibrogenic cell type. usually more advanced in with type 2 diabetes mellitus, indicating all diabetic should be screened for disease. Although there been substantial progress clarifying pathways no approved therapies yet, but current research seeks uncover driving hopes identifying new therapeutic targets. Emerging molecular methods, especially single sequencing technologies, revolutionizing our ability clarify mechanisms underlying MASLD-associated HCC.

Language: Английский

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Oligonucleotide therapies for nonalcoholic steatohepatitis

Molecular Therapy — Nucleic Acids, Journal Year: 2024, Volume and Issue: 35(2), P. 102184 - 102184

Published: March 30, 2024

Nonalcoholic steatohepatitis (NASH) represents a severe disease subtype of nonalcoholic fatty liver (NAFLD) that is thought to be highly associated with systemic metabolic abnormalities. It characterized by series substantial damage, including hepatocellular steatosis, inflammation, and fibrosis. The end stage NASH, in some cases, may result cirrhosis carcinoma (HCC). Nowadays large number investigations are actively under way test various therapeutic strategies, emerging oligonucleotide drugs (e.g., antisense oligonucleotide, small interfering RNA, microRNA, mimic/inhibitor activating RNA) have shown high potential treating this fatal disease. This article systematically reviews the pathogenesis NASH/NAFLD, promising druggable targets proven current studies chemical compounds or biological drug development, feasibility limitations oligonucleotide-based approaches clinical pre-clinical studies.

Language: Английский

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