Understanding the cellular interactome of non-alcoholic fatty liver disease

JHEP Reports, Год журнала: 2022, Номер 4(8), С. 100524 - 100524

Опубликована: Июнь 15, 2022

Summary

Non-alcoholic fatty liver disease (NAFLD) is reaching epidemic proportions, with a global prevalence of 25% in the adult population. steatohepatitis (NASH), which can lead to cirrhosis, has become leading indication for transplantation both Europe and USA. Liver fibrosis consequence sustained, iterative injury, main determinant outcomes NASH. The possesses remarkable inherent plasticity, regress when injurious agent removed, thus providing opportunities alter long-term through therapeutic interventions. Although hepatocyte injury key driver NASH, multiple other cell lineages within hepatic fibrotic niche play major roles perpetuation inflammation, mesenchymal activation, extracellular matrix accumulation as well resolution. constituents this cellular interactome, how various subpopulations interact drive fibrogenesis an area active research. Important components include endothelial cells, macrophages, passaging immune populations myofibroblasts. In review, we will describe rapidly evolving technologies such single-cell genomics, spatial transcriptomics ligand-receptor analyses are transforming our understanding interactome NAFLD/NASH, new, high-resolution information being leveraged develop rational new therapies patients

Язык: Английский

---

Role of immune responses in the development of NAFLD-associated liver cancer and prospects for therapeutic modulation

Journal of Hepatology, Год журнала: 2023, Номер 79(2), С. 538 - 551

Опубликована: Март 7, 2023

The liver is the central metabolic organ of body, regulating energy and lipid metabolism, while also having potent immunological functions. Overwhelming capacity via obesity a sedentary lifestyle leads to hepatic accumulation, chronic necro-inflammation, enhanced mitochondrial/endoplasmic reticulum stress development non-alcoholic fatty disease (NAFLD), its more severe form steatohepatitis (NASH). Based on an improved understanding pathophysiological mechanisms, specifically targeting pathways prevent or slow down progression NAFLD cancer will become possible. Genetic/environmental factors are known contribute NASH cancer. complex pathophysiology NAFLD-NASH reflected by environmental factors, particularly gut microbiome products. NAFLD-associated HCC most often occurs in context chronically inflamed cirrhotic liver. Recognition alarmins metabolites derived from microbiota metabolically injured create strong inflammatory milieu supported innate adaptive immunity. Several recent studies indicate that steatosis induces auto-aggressive CD8+CXCR6+PD1+ T cells eliminate parenchymal non-parenchymal antigen-independent manner. This promotes damage pro-tumorigenic environment. possess exhausted, hyperactivated, resident phenotype; they trigger transition might be responsible for weaker responses immune checkpoint inhibitors - particular atezolizumab/bevacizumab. Here, we provide overview NASH-related inflammation/pathogenesis, focusing new discoveries role cells. review discusses preventive measures halt therapeutic strategies manage patients with NASH-HCC.

Язык: Английский

---

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

Science Translational Medicine, Год журнала: 2023, Номер 15(716)

Опубликована: Окт. 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.

Язык: Английский

---

Immune cell dynamics deconvoluted by single-cell RNA sequencing in normothermic machine perfusion of the liver

Nature Communications, Год журнала: 2023, Номер 14(1)

Опубликована: Апрель 21, 2023

Normothermic machine perfusion (NMP) has emerged as an innovative organ preservation technique. Developing understanding for the donor immune cell composition and its dynamic changes during NMP is essential. We aimed a comprehensive characterization of (sub)populations, trafficking cytokine release liver NMP. Single-cell transcriptome profiling human livers prior to, after transplantation shows abundance CXC chemokine receptor 1+/2+ (CXCR1+/CXCR2+) neutrophils, which significantly decreased This paralleled by large efflux passenger leukocytes with neutrophil predominance in perfusate. During NMP, neutrophils shift from pro-inflammatory state towards aged/chronically activated/exhausted phenotype, while anti-inflammatory/tolerogenic monocytes/macrophages are increased. herein describe dynamics repertoire, phenotypic shifts dominance potentially contribute to inflammatory response. Our findings may serve resource initiate future immune-interventional studies.

Язык: Английский

---

Amphiregulin from regulatory T cells promotes liver fibrosis and insulin resistance in non-alcoholic steatohepatitis

Immunity, Год журнала: 2024, Номер 57(2), С. 303 - 318.e6

Опубликована: Фев. 1, 2024

Язык: Английский

---

Hepatic Stellate Cell-Immune Interactions in NASH

Frontiers in Endocrinology, Год журнала: 2022, Номер 13

Опубликована: Июнь 9, 2022

Nonalcoholic fatty liver disease (NAFLD) is the dominant cause of worldwide. steatohepatitis (NASH), a more aggressive presentation NAFLD, characterized by severe hepatocellular injury, inflammation, and fibrosis. Chronic inflammation heightened immune cell activity have emerged as hallmark features NASH key drivers fibrosis through activation hepatic stellate cells (HSCs). Recent advances in our understanding molecular cellular pathways highlighted extensive crosstalk between HSCs populations that strongly influences activity. Here, we review these findings, emphasizing roles immunity cell-cell interactions, exciting areas for future investigation.

Язык: Английский

---

Senescent cells suppress macrophage-mediated corpse removal via upregulation of the CD47-QPCT/L axis

The Journal of Cell Biology, Год журнала: 2022, Номер 222(2)

Опубликована: Ноя. 5, 2022

Progressive accrual of senescent cells in aging and chronic diseases is associated with detrimental effects tissue homeostasis. We found that fibroblasts epithelia were not only refractory to macrophage-mediated engulfment removal, but they also paralyzed the ability macrophages remove bystander apoptotic corpses. Senescent cell-mediated efferocytosis suppression (SCES) was independent senescence-associated secretory phenotype (SASP) instead required direct contact between cells. SCES involved augmented cell expression CD47 coinciding increased CD47-modifying enzymes QPCT/L. reversible by interfering SIRPα-CD47-SHP-1 axis or QPCT/L activity. While human mouse vitro vivo, another ITIM-containing protein, CD24, contributed specifically epithelial where it compensated for genetic deficiency CD47. Thus, CD24 link pathogenic homeostatic macrophage functions, such as efferocytosis, which we hypothesize must occur efficiently maintain

Язык: Английский

---

Hepatic Stellate Cells: Dictating Outcome in Nonalcoholic Fatty Liver Disease

Cellular and Molecular Gastroenterology and Hepatology, Год журнала: 2023, Номер 15(6), С. 1277 - 1292

Опубликована: Янв. 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

Язык: Английский

---

A single-nucleus transcriptomic atlas of primate liver aging uncovers the pro-senescence role of SREBP2 in hepatocytes

Protein & Cell, Год журнала: 2023, Номер 15(2), С. 98 - 120

Опубликована: Июнь 28, 2023

Aging increases the risk of liver diseases and systemic susceptibility to aging-related diseases. However, cell type-specific changes underlying mechanism aging in higher vertebrates remain incompletely characterized. Here, we constructed first single-nucleus transcriptomic landscape primate aging, which resolved gene expression fluctuation hepatocytes across three zonations detected aberrant cell-cell interactions between niche cells. Upon in-depth dissection this rich dataset, identified impaired lipid metabolism upregulation chronic inflammation-related genes prominently associated with declined functions during aging. In particular, hyperactivated sterol regulatory element-binding protein (SREBP) signaling was a hallmark aged liver, consequently, forced activation SREBP2 human primary recapitulated vivo phenotypes, manifesting as detoxification accelerated cellular senescence. This study expands our knowledge informs development diagnostics therapeutic interventions for

Язык: Английский

---

Spatial genomics: mapping human steatotic liver disease

Nature Reviews Gastroenterology & Hepatology, Год журнала: 2024, Номер 21(9), С. 646 - 660

Опубликована: Апрель 23, 2024

Язык: Английский

---