Current perspectives on the pathophysiology of metabolic associated fatty liver disease: are macrophages a viable target for therapy?

References

• Marchesini G, Brizi M, Bianchi G, et al. Nonalcoholic fatty liver disease: a feature of the metabolic syndrome. Diabetes. 2001 Aug;50(8):1844.-50.
   PubMed Web of Science ®Google Scholar
• Eslam M, Newsome PN, Anstee QM, et al. A new definition for metabolic associated fatty liver disease: an international expert consensus statement. J Hepatol. 2020;73(1):202–209. DOI:10.1016/j.jhep.2020.03.039.
   Web of Science ®Google Scholar
• Eslam M, Sanyal AJ, George J. MAFLD: a consensus-driven proposed nomenclature for metabolic associated fatty liver disease. Gastroenterology. 2020;158(7):1999–2014.e1. DOI:10.1053/j.gastro.2019.11.312.
   Web of Science ®Google Scholar
• Younossi ZM, Koenig AB, Abdelatif D, et al. Global epidemiology of nonalcoholic fatty liver disease-Meta-analytic assessment of prevalence, incidence, and outcomes. Hepatology. 2016;64(1):73–84.
   PubMed Web of Science ®Google Scholar
• Nobili V, Alkhouri N, Alisi A, et al. Nonalcoholic fatty liver disease: a challenge for pediatricians. JAMA Pediatr. 2015;169(2):170–176.
   PubMed Web of Science ®Google Scholar
• Kazankov K, Jorgensen SMD, Thomsen KL, et al. The role of macrophages in nonalcoholic fatty liver disease and nonalcoholic steatohepatitis. Nat Rev Gastroenterol Hepatol. 2019;16(3):145–159.
   PubMed Web of Science ®Google Scholar
• Schuppan D, Surabattula R, Wang XY. Determinants of fibrosis progression and regression in NASH. J Hepatol. 2018;68(2):238–250.
   PubMed Web of Science ®Google Scholar
• Schwabe RF, Tabas I, Pajvani UB. Mechanisms of Fibrosis Development in NASH. Gastroenterology. 2020;158(7):1913–1928. DOI:10.1053/j.gastro.2019.11.311.
   Google Scholar
• Alharthi J, Latchoumanin O, George J, et al. Macrophages in metabolic associated fatty liver disease. World J Gastroenterol. 2020;26(16):1861–1878.
   PubMed Web of Science ®Google Scholar
• Lopez BG, Tsai MS, Baratta JL, et al. Characterization of Kupffer cells in livers of developing mice. Comp Hepatol. 2011;10(1):2.
   PubMedGoogle Scholar
• Kinoshita M, Uchida T, Sato A, et al. Characterization of two F4/80-positive Kupffer cell subsets by their function and phenotype in mice. J Hepatol. 2010;53(5):903–910.
   PubMed Web of Science ®Google Scholar
• Chistiakov DA, Killingsworth MC, Myasoedova VA, et al. CD68/macrosialin: not just a histochemical marker. Lab Invest. 2017;97(1):4–13.
   PubMed Web of Science ®Google Scholar
• Adams LA, Anstee QM, Tilg H, et al. Non-alcoholic fatty liver disease and its relationship with cardiovascular disease and other extrahepatic diseases. Gut. 2017;66(6):1138–1153.
   PubMed Web of Science ®Google Scholar
• Mills CD, Kincaid K, Alt JM, et al. M-1/M-2 macrophages and the Th1/Th2 paradigm. J Immunol. 2000;164(12):6166–6173.
   PubMed Web of Science ®Google Scholar
• Aizarani N, Saviano A, Sagar, et al. A human liver cell atlas reveals heterogeneity and epithelial progenitors. Nature. 2019;572(7768):199–204.
   PubMed Web of Science ®Google Scholar
• Krenkel O, Hundertmark J, Abdallah AT, et al. Myeloid cells in liver and bone marrow acquire a functionally distinct inflammatory phenotype during obesity-related steatohepatitis. Gut. 2020;69(3):551–563.
   PubMed Web of Science ®Google Scholar
• MacParland SA, Liu JC, Ma XZ, et al. Single cell RNA sequencing of human liver reveals distinct intrahepatic macrophage populations. Nat Commun. 2018;9(1):4383.
   PubMed Web of Science ®Google Scholar
• Gomez Perdiguero E, Klapproth K, Schulz C, et al. Tissue-resident macrophages originate from yolk-sac-derived erythro-myeloid progenitors. Nature. 2015;518(7540):547–551.
   PubMed Web of Science ®Google Scholar
• Mass E, Ballesteros I, Farlik M, et al. Specification of tissue-resident macrophages during organogenesis. Science. 2016;353(6304):aaf4238. DOI:10.1126/science.aaf4238.
   PubMed Web of Science ®Google Scholar
• Heymann F, Peusquens J, Ludwig-Portugall I, et al. Liver inflammation abrogates immunological tolerance induced by Kupffer cells. Hepatology. 2015;62(1):279–291.
   PubMed Web of Science ®Google Scholar
• Kanneganti TD, Lamkanfi M, Nunez G. Intracellular NOD-like receptors in host defense and disease. Immunity. 2007;27(4):549–559.
   PubMed Web of Science ®Google Scholar
• Nakamoto N, Kanai T. Role of toll-like receptors in immune activation and tolerance in the liver. Front Immunol. 2014;5:221.
   PubMed Web of Science ®Google Scholar
• Scott CL, Zheng F, De Baetselier P, et al. Bone marrow-derived monocytes give rise to self-renewing and fully differentiated Kupffer cells. Nat Commun. 2016;7:10321.
   PubMed Web of Science ®Google Scholar
• Fogg DK, Sibon C, Miled C, et al. A clonogenic bone marrow progenitor specific for macrophages and dendritic cells. Science. 2006;311(5757):83–87.
   PubMed Web of Science ®Google Scholar
• Miura K, Yang L, van Rooijen N, et al. Hepatic recruitment of macrophages promotes nonalcoholic steatohepatitis through CCR2. Am J Physiol Gastrointest Liver Physiol. 2012;302(11):G1310–G1321.
   PubMed Web of Science ®Google Scholar
• Mossanen JC, Krenkel O, Ergen C, et al. Chemokine (C-C motif) receptor 2-positive monocytes aggravate the early phase of acetaminophen-induced acute liver injury. Hepatology. 2016;64(5):1667–1682.
   PubMed Web of Science ®Google Scholar
• Martinez FO, Gordon S. The M1 and M2 paradigm of macrophage activation: time for reassessment. F1000Prime Rep. 2014;6:13.
   PubMedGoogle Scholar
• Tacke F. Targeting hepatic macrophages to treat liver diseases. J Hepatol. 2017;66(6):1300–1312.
   PubMed Web of Science ®Google Scholar
• Dou L, Shi X, He X, et al. Macrophage Phenotype and Function in Liver Disorder. Front Immunol. 2019;10:3112.
   PubMed Web of Science ®Google Scholar
• MacParland SA, Tsoi KM, Ouyang B, et al. Phenotype Determines Nanoparticle Uptake by Human Macrophages from Liver and Blood. ACS Nano. 2017;11(3):2428–2443.
   PubMed Web of Science ®Google Scholar
• Montoya D, Mehta M, Ferguson BG, et al. Plasticity of antimicrobial and phagocytic programs in human macrophages. Immunology. 2019;156(2):164–173.
   PubMed Web of Science ®Google Scholar
• Beattie L, Sawtell A, Mann J, et al. Bone marrow-derived and resident liver macrophages display unique transcriptomic signatures but similar biological functions. J Hepatol. 2016;65(4):758–768.
   PubMed Web of Science ®Google Scholar
• Ramachandran P, Pellicoro A, Vernon MA, et al. Differential Ly-6C expression identifies the recruited macrophage phenotype, which orchestrates the regression of murine liver fibrosis. Proc Natl Acad Sci U S A. 2012;109(46):E3186–E3195.
   PubMed Web of Science ®Google Scholar
• Neuschwander-Tetri BA. Hepatic lipotoxicity and the pathogenesis of nonalcoholic steatohepatitis: the central role of nontriglyceride fatty acid metabolites. Hepatology. 2010;52(2):774–788.
   PubMed Web of Science ®Google Scholar
• Machado MV, Diehl AM. Pathogenesis of Nonalcoholic Steatohepatitis. Gastroenterology. 2016;150(8):1769–1777.
   PubMed Web of Science ®Google Scholar
• Boden G. Obesity and free fatty acids. Endocrinol Metab Clin North Am. 2008;37(3):635–ix.
   PubMed Web of Science ®Google Scholar
• de Almeida IT, Cortez-Pinto H, Fidalgo G, et al. Plasma total and free fatty acids composition in human non-alcoholic steatohepatitis. Clin Nutr. 2002;21(3):219–223.
   PubMed Web of Science ®Google Scholar
• Fujita K, Nozaki Y, Wada K, et al. Dysfunctional very-low-density lipoprotein synthesis and release is a key factor in nonalcoholic steatohepatitis pathogenesis. Hepatology. 2009;50(3):772–780.
   PubMed Web of Science ®Google Scholar
• Pan J, Ou Z, Cai C, et al. Fatty acid activates NLRP3 inflammasomes in mouse Kupffer cells through mitochondrial DNA release. Cell Immunol. 2018;332:111–120.
   PubMed Web of Science ®Google Scholar
• Wang X, de Carvalho Ribeiro M, Iracheta-Vellve A, et al. Macrophage-Specific Hypoxia-Inducible Factor-1alpha Contributes to Impaired Autophagic Flux in Nonalcoholic Steatohepatitis. Hepatology. 2019;69(2):545–563.
   PubMed Web of Science ®Google Scholar
• Bernales S, McDonald KL, Walter P. Autophagy counterbalances endoplasmic reticulum expansion during the unfolded protein response. PLoS Biol. 2006;4(12):e423–e423.
   PubMed Web of Science ®Google Scholar
• Yoo W, Noh KH, Ahn JH, et al. HIF-1α expression as a protective strategy of HepG2 cells against fatty acid-induced toxicity. J Cell Biochem. 2014;115(6):1147–1158.
   PubMed Web of Science ®Google Scholar
• Czaja MJ. Function of Autophagy in Nonalcoholic Fatty Liver Disease. Dig Dis Sci. 2016;61(5):1304–1313.
   PubMed Web of Science ®Google Scholar
• Leroux A, Ferrere G, Godie V, et al. Toxic lipids stored by Kupffer cells correlates with their pro-inflammatory phenotype at an early stage of steatohepatitis. J Hepatol. 2012;57(1):141–149.
   PubMed Web of Science ®Google Scholar
• Yu Y, Liu Y, An W, et al. STING-mediated inflammation in Kupffer cells contributes to progression of nonalcoholic steatohepatitis. J Clin Invest. 2019;129(2):546–555.
   PubMed Web of Science ®Google Scholar
• Garcia-Martinez I, Santoro N, Chen Y, et al. Hepatocyte mitochondrial DNA drives nonalcoholic steatohepatitis by activation of TLR9. J Clin Invest. 2016;126(3):859–864.
   PubMed Web of Science ®Google Scholar
• Miura K, Kodama Y, Inokuchi S, et al. Toll-like receptor 9 promotes steatohepatitis by induction of interleukin-1beta in mice. Gastroenterology. 2010;139(1):323–334.e327.
   PubMed Web of Science ®Google Scholar
• Du X, Wu Z, Xu Y, et al. Increased Tim-3 expression alleviates liver injury by regulating macrophage activation in MCD-induced NASH mice. Cell Mol Immunol. 2019;16(11):878–886.
   PubMed Web of Science ®Google Scholar
• Liu W, Bai F, Wang H, et al. Tim-4 Inhibits NLRP3 Inflammasome via the LKB1/AMPKalpha Pathway in Macrophages. J Immunol. 2019;203(4):990–1000.
   PubMed Web of Science ®Google Scholar
• Wiest R, Albillos A, Trauner M, et al. Targeting the gut-liver axis in liver disease. J Hepatol. 2017;67(5):1084–1103.
   PubMed Web of Science ®Google Scholar
• Frasinariu OE, Ceccarelli S, Alisi A, et al. Gut-liver axis and fibrosis in nonalcoholic fatty liver disease: an input for novel therapies. Dig Liver Dis. 2013;45(7):543–551.
   PubMedGoogle Scholar
• Miele L, Valenza V, La Torre G, et al. Increased intestinal permeability and tight junction alterations in nonalcoholic fatty liver disease. Hepatology. 2009;49(6):1877–1887.
   PubMed Web of Science ®Google Scholar
• Shanab AA, Scully P, Crosbie O, et al. Small intestinal bacterial overgrowth in nonalcoholic steatohepatitis: association with toll-like receptor 4 expression and plasma levels of interleukin 8. Dig Dis Sci. 2011;56(5):1524–1534.
   PubMed Web of Science ®Google Scholar
• Miura K, Ohnishi H. Role of gut microbiota and Toll-like receptors in nonalcoholic fatty liver disease. World J Gastroenterol. 2014;20(23):7381–7391.
   PubMed Web of Science ®Google Scholar
• Pendyala S, Walker JM, Holt PR. A high-fat diet is associated with endotoxemia that originates from the gut. Gastroenterology. 2012;142(5):1100–1101.e1102.
   PubMed Web of Science ®Google Scholar
• Rivera CA, Adegboyega P, van Rooijen N, et al. Toll-like receptor-4 signaling and Kupffer cells play pivotal roles in the pathogenesis of non-alcoholic steatohepatitis. J Hepatol. 2007;47(4):571–579.
   PubMed Web of Science ®Google Scholar
• Ogawa Y, Imajo K, Honda Y, et al. Palmitate-induced lipotoxicity is crucial for the pathogenesis of nonalcoholic fatty liver disease in cooperation with gut-derived endotoxin. Sci Rep. 2018;8(1):11365.
   PubMedGoogle Scholar
• Vespasiani-Gentilucci U, Carotti S, Perrone G, et al. Hepatic toll-like receptor 4 expression is associated with portal inflammation and fibrosis in patients with NAFLD. Liver Int. 2015;35(2):569–581.
   PubMed Web of Science ®Google Scholar
• Budick-Harmelin N, Dudas J, Demuth J, et al. Triglycerides potentiate the inflammatory response in rat Kupffer cells. Antioxid Redox Signal. 2008;10(12):2009–2022.
   PubMed Web of Science ®Google Scholar
• Anakk S, Bhosale M, Schmidt VA, et al. Bile acids activate YAP to promote liver carcinogenesis. Cell Rep. 2013;5(4):1060–1069.
   PubMed Web of Science ®Google Scholar
• Kim MK, Park JY, Kang YN. Tumorigenic role of YAP in hepatocellular carcinogenesis is involved in SHP2 whose function is different in vitro and in vivo. Pathol Res Pract. 2018;214(7):1031–1039.
   PubMed Web of Science ®Google Scholar
• Song K, Kwon H, Han C, et al. YAP in Kupffer cells enhances the production of pro-inflammatory cytokines and promotes the development of non-alcoholic steatohepatitis. Hepatology. 20192020;72(1):72–87. DOI:10.1002/hep.30990.
   Google Scholar
• Orci LA, Kreutzfeldt M, Goossens N, et al. Tolerogenic properties of liver macrophages in non-alcoholic steatohepatitis. Liver Int. 2020;40(3):609–621. DOI:10.1111/liv.14336.
   Web of Science ®Google Scholar
• Niu B, He K, Li P, et al. SIRT1 upregulation protects against liver injury induced by a HFD through inhibiting CD36 and the NFkappaB pathway in mouse kupffer cells. Mol Med Rep. 2018;18(2):1609–1615.
   PubMed Web of Science ®Google Scholar
• Cai B, Dongiovanni P, Corey KE, et al. Macrophage MerTK Promotes Liver Fibrosis in Nonalcoholic Steatohepatitis. Cell Metab. 2020;31(2):406–421.e407.
   PubMed Web of Science ®Google Scholar
• Puengel T, Krenkel O, Kohlhepp M, et al. Differential impact of the dual CCR2/CCR5 inhibitor cenicriviroc on migration of monocyte and lymphocyte subsets in acute liver injury. PLoS One. 2017;12(9):e0184694–e0184694.
   PubMed Web of Science ®Google Scholar
• Kanda H, Tateya S, Tamori Y, et al. MCP-1 contributes to macrophage infiltration into adipose tissue, insulin resistance, and hepatic steatosis in obesity. J Clin Invest. 2006;116(6):1494–1505.
   PubMed Web of Science ®Google Scholar
• Lefere S, Devisscher L, Tacke F. Targeting CCR2/5 in the treatment of nonalcoholic steatohepatitis (NASH) and fibrosis: opportunities and challenges. Expert Opin Investig Drugs. 2020;29(2):89–92.
   PubMed Web of Science ®Google Scholar
• Zhong L, Huang L, Xue Q, et al. Cell-specific elevation of Runx2 promotes hepatic infiltration of macrophages by upregulating MCP-1 in high-fat diet-induced mice NAFLD. J Cell Biochem. 2019;10.1002/jcb.28456. DOI:10.1002/jcb.28456.
   Web of Science ®Google Scholar
• Baeck C, Wehr A, Karlmark KR, et al. Pharmacological inhibition of the chemokine CCL2 (MCP-1) diminishes liver macrophage infiltration and steatohepatitis in chronic hepatic injury. Gut. 2012;61(3):416.
   PubMed Web of Science ®Google Scholar
• Tosello-Trampont A-C, Landes SG, Nguyen V, et al. Kuppfer cells trigger nonalcoholic steatohepatitis development in diet-induced mouse model through tumor necrosis factor-α production. J Biol Chem. 2012;287(48):40161–40172.
   PubMed Web of Science ®Google Scholar
• Krenkel O, Puengel T, Govaere O, et al. Therapeutic inhibition of inflammatory monocyte recruitment reduces steatohepatitis and liver fibrosis. Hepatology. 2018;67(4):1270–1283.
   PubMed Web of Science ®Google Scholar
• Lefebvre E, Moyle G, Reshef R, et al. Antifibrotic Effects of the Dual CCR2/CCR5 Antagonist Cenicriviroc in Animal Models of Liver and Kidney Fibrosis. PLoS One. 2016;11(6):e0158156.
   PubMed Web of Science ®Google Scholar
• Hirsova P, Ibrahim SH, Verma VK, et al. Extracellular vesicles in liver pathobiology: small particles with big impact. Hepatology. 2016;64(6):2219–2233.
   PubMed Web of Science ®Google Scholar
• Guo Q, Furuta K, Lucien F, et al. Integrin beta1-enriched extracellular vesicles mediate monocyte adhesion and promote liver inflammation in murine NASH. J Hepatol. 2019;71(6):1193–1205.
   PubMed Web of Science ®Google Scholar
• Liao CY, Song MJ, Gao Y, et al. Hepatocyte-Derived Lipotoxic Extracellular Vesicle Sphingosine 1-Phosphate Induces Macrophage Chemotaxis. Front Immunol. 2018;9:2980.
   PubMed Web of Science ®Google Scholar
• Kakazu E, Mauer AS, Yin M, et al. Hepatocytes release ceramide-enriched pro-inflammatory extracellular vesicles in an IRE1alpha-dependent manner. J Lipid Res. 2016;57(2):233–245.
   PubMed Web of Science ®Google Scholar
• Kong Q, Li N, Cheng H, et al. HSPA12A Is a Novel Player in Nonalcoholic Steatohepatitis via Promoting Nuclear PKM2-Mediated M1 Macrophage Polarization. Diabetes. 2019;68(2):361–376.
   PubMed Web of Science ®Google Scholar
• Devhare PB, Ray RB. Extracellular vesicles: novel mediator for cell to cell communications in liver pathogenesis. Mol Aspects Med. 2018;60:115–122.
   PubMed Web of Science ®Google Scholar
• Liu XL, Pan Q, Cao HX, et al. Lipotoxic Hepatocyte-Derived Exosomal miR-192-5p Activates Macrophages via Rictor/Akt/FoxO1 Signaling in NAFLD. Hepatology. 2020;72(2):454–469. DOI:10.1002/hep.31050.
   Google Scholar
• Wang YC, Ma HD, Yin XY, et al. Forkhead Box O1 Regulates Macrophage Polarization Following Staphylococcus aureus Infection: experimental Murine Data and Review of the Literature. Clin Rev Allergy Immunol. 2016;51(3):353–369.
   PubMed Web of Science ®Google Scholar
• Makdissi A, Ghanim H, Vora M, et al. Sitagliptin exerts an antiinflammatory action. J Clin Endocrinol Metab. 2012;97(9):3333–3341.
   PubMed Web of Science ®Google Scholar
• Shirakawa J, Fujii H, Ohnuma K, et al. Diet-induced adipose tissue inflammation and liver steatosis are prevented by DPP-4 inhibition in diabetic mice. Diabetes. 2011;60(4):1246–1257.
   PubMed Web of Science ®Google Scholar
• Yang Y, Lu Y, Han F, et al. Saxagliptin regulates M1/M2 macrophage polarization via CaMKKbeta/AMPK pathway to attenuate NAFLD. Biochem Biophys Res Commun. 2018;503(3):1618–1624.
   PubMed Web of Science ®Google Scholar
• Romero-Gómez M, Zelber-Sagi S, Trenell M. Treatment of NAFLD with diet, physical activity and exercise. J Hepatol. 2017;67(4):829–846.
   PubMed Web of Science ®Google Scholar
• Rinella ME, Sanyal AJ. Management of NAFLD: a stage-based approach. Nat Rev Gastroenterol Hepatol. 2016;13(4):196–205.
   PubMed Web of Science ®Google Scholar
• Cheong H, Lee SS, Lee JS, et al. Phagocytic function of Kupffer cells in mouse nonalcoholic fatty liver disease models: evaluation with superparamagnetic iron oxide. J Magn Reson Imaging. 2015;41(5):1218–1227.
   PubMed Web of Science ®Google Scholar
• Tsujimoto T, Kawaratani H, Kitazawa T, et al. Decreased phagocytic activity of Kupffer cells in a rat nonalcoholic steatohepatitis model. World J Gastroenterol. 2008;14(39):6036–6043.
   PubMed Web of Science ®Google Scholar
• Komine S, Akiyama K, Warabi E, et al. Exercise training enhances in vivo clearance of endotoxin and attenuates inflammatory responses by potentiating Kupffer cell phagocytosis. Sci Rep. 2017;7(1):11977.
   PubMedGoogle Scholar
• Kazankov K, Moller HJ, Lange A, et al. The macrophage activation marker sCD163 is associated with changes in NAFLD and metabolic profile during lifestyle intervention in obese children. Pediatr Obes. 2015;10(3):226–233.
   PubMed Web of Science ®Google Scholar
• Rodgaard-Hansen S, St George A, Kazankov K, et al. Effects of lifestyle intervention on soluble CD163, a macrophage activation marker, in patients with non-alcoholic fatty liver disease. Scand J Clin Lab Invest. 2017;77(7):498–504.
   PubMed Web of Science ®Google Scholar
• Kazankov K, Tordjman J, Moller HJ, et al. Macrophage activation marker soluble CD163 and non-alcoholic fatty liver disease in morbidly obese patients undergoing bariatric surgery. J Gastroenterol Hepatol. 2015;30(8):1293–1300.
   PubMed Web of Science ®Google Scholar
• Ho MK, Springer TA. Mac-1 antigen: quantitative expression in macrophage populations and tissues, and immunofluorescent localization in spleen. J Immunol. 1982;128(5):2281.
   PubMed Web of Science ®Google Scholar
• de Oliveira FL, Panera N, De Stefanis C, et al. The Number of Liver Galectin-3 Positive Cells Is Dually Correlated with NAFLD Severity in Children. Int J Mol Sci. 2019;20:14.
   Web of Science ®Google Scholar
• Li LC, Li J, Gao J. Functions of galectin-3 and its role in fibrotic diseases. J Pharmacol Exp Ther. 2014;351(2):336–343.
   PubMed Web of Science ®Google Scholar
• Iacobini C, Menini S, Ricci C, et al. Galectin-3 ablation protects mice from diet-induced NASH: a major scavenging role for galectin-3 in liver. J Hepatol. 2011;54(5):975–983.
   PubMed Web of Science ®Google Scholar
• Jeftic I, Jovicic N, Pantic J, et al. Galectin-3 Ablation Enhances Liver Steatosis, but Attenuates Inflammation and IL-33-Dependent Fibrosis in Obesogenic Mouse Model of Nonalcoholic Steatohepatitis. Mol Med. 2015;21(1):453–465.
   PubMedGoogle Scholar
• Harrison SA, Marri SR, Chalasani N, et al. Randomised clinical study: GR-MD-02, a galectin-3 inhibitor, vs. placebo in patients having non-alcoholic steatohepatitis with advanced fibrosis. Aliment Pharmacol Ther. 2016;44(11–12):1183–1198.
   PubMed Web of Science ®Google Scholar
• Chalasani N, Abdelmalek MF, Garcia-Tsao G, et al. Effects of Belapectin, an Inhibitor of Galectin-3, in Patients With Nonalcoholic Steatohepatitis With Cirrhosis and Portal Hypertension. Gastroenterology. 2020;158(5):1334–1345.e5. DOI:10.1053/j.gastro.2019.11.296.
   Google Scholar
• Study Evaluating the Efficacy and Safety of Belapectin (GR-MD-02) for the Prevention of Esophageal Varices in NASH Cirrhosis. (Ed.^(Eds).
   Google Scholar
• Friedman SL, Ratziu V, Harrison SA, et al. A randomized, placebo-controlled trial of cenicriviroc for treatment of nonalcoholic steatohepatitis with fibrosis. Hepatology. 2018;67(5):1754–1767.
   PubMed Web of Science ®Google Scholar
• AURORA: Phase 3 Study for the Efficacy and Safety of CVC for the Treatment of Liver Fibrosis in Adults With NASH. (Ed.^(Eds).
   Google Scholar
• Karpen SJ. Do therapeutic bile acids hit the sweet spot of glucose metabolism in NAFLD? Gastroenterology. 2013;145(3):508–510.
   PubMed Web of Science ®Google Scholar
• Trauner M, Claudel T, Fickert P, et al. Bile acids as regulators of hepatic lipid and glucose metabolism. Dig Dis. 2010;28(1):220–224.
   PubMed Web of Science ®Google Scholar
• Yao J, Zhou CS, Ma X, et al. FXR agonist GW4064 alleviates endotoxin-induced hepatic inflammation by repressing macrophage activation. World J Gastroenterol. 2014;20(39):14430–14441.
   PubMed Web of Science ®Google Scholar
• McMahan RH, Wang XX, Cheng LL, et al. Bile acid receptor activation modulates hepatic monocyte activity and improves nonalcoholic fatty liver disease. J Biol Chem. 2013;288(17):11761–11770.
   PubMed Web of Science ®Google Scholar
• Neuschwander-Tetri BA, Loomba R, Sanyal AJ, et al. Farnesoid X nuclear receptor ligand obeticholic acid for non-cirrhotic, non-alcoholic steatohepatitis (FLINT): a multicentre, randomised, placebo-controlled trial. Lancet. 2015;385(9972):956–965.
   PubMed Web of Science ®Google Scholar
• Younossi ZM, Ratziu V, Loomba R, et al. Obeticholic acid for the treatment of non-alcoholic steatohepatitis: interim analysis from a multicentre, randomised, placebo-controlled phase 3 trial. Lancet. 2019;394(10215):2184–2196.
   PubMed Web of Science ®Google Scholar
• Armstrong MJ, Hull D, Guo K, et al. Glucagon-like peptide 1 decreases lipotoxicity in non-alcoholic steatohepatitis. J Hepatol. 2016;64(2):399–408.
   PubMed Web of Science ®Google Scholar
• Li Z, Feng -P-P, Zhao Z-B, et al. Liraglutide protects against inflammatory stress in non-alcoholic fatty liver by modulating Kupffer cells M2 polarization via cAMP-PKA-STAT3 signaling pathway. Biochem Biophys Res Commun. 2019;510(1):20–26.
   PubMed Web of Science ®Google Scholar
• Mells JE, Fu PP, Sharma S, et al. Glp-1 analog, liraglutide, ameliorates hepatic steatosis and cardiac hypertrophy in C57BL/6J mice fed a Western diet. Am J Physiol Gastrointest Liver Physiol. 2012;302(2):G225–235.
   PubMed Web of Science ®Google Scholar
• Yang Y, Fang H, Xu G, et al. Liraglutide improves cognitive impairment via the AMPK and PI3K/Akt signaling pathways in type 2 diabetic rats. Mol Med Rep. 2018;18(2):2449–2457.
   PubMed Web of Science ®Google Scholar
• Hogan AE, Gaoatswe G, Lynch L, et al. Glucagon-like peptide 1 analogue therapy directly modulates innate immune-mediated inflammation in individuals with type 2 diabetes mellitus. Diabetologia. 2014;57(4):781–784.
   PubMed Web of Science ®Google Scholar
• Armstrong MJ, Gaunt P, Aithal GP, et al. Liraglutide safety and efficacy in patients with non-alcoholic steatohepatitis (LEAN): a multicentre, double-blind, randomised, placebo-controlled phase 2 study. Lancet. 2016;387(10019):679–690.
   PubMed Web of Science ®Google Scholar
• Investigation of Efficacy and Safety of Three Dose Levels of Subcutaneous Semaglutide Once Daily Versus Placebo in Subjects With Non-alcoholic Steatohepatitis. (Ed.^(Eds).
   Google Scholar
• Luo W, Xu Q, Wang Q, et al. Effect of modulation of PPAR-gamma activity on Kupffer cells M1/M2 polarization in the development of non-alcoholic fatty liver disease. Sci Rep. 2017;7:44612.
   PubMed Web of Science ®Google Scholar
• Odegaard JI, Ricardo-Gonzalez RR, Goforth MH, et al. Macrophage-specific PPARgamma controls alternative activation and improves insulin resistance. Nature. 2007;447(7148):1116–1120.
   PubMed Web of Science ®Google Scholar
• Cusi K, Orsak B, Bril F, et al. Long-term pioglitazone treatment for patients with nonalcoholic steatohepatitis and prediabetes or type 2 diabetes mellitus: a randomized trial. Ann Intern Med. 2016;165(5):305–315.
   PubMed Web of Science ®Google Scholar
• Boettcher E, Csako G, Pucino F, et al. Meta-analysis: pioglitazone improves liver histology and fibrosis in patients with non-alcoholic steatohepatitis. Aliment Pharmacol Ther. 2012;35(1):66–75.
   PubMed Web of Science ®Google Scholar
• He S, Tang YH, Zhao G, et al. Pioglitazone prescription increases risk of bladder cancer in patients with type 2 diabetes: an updated meta-analysis. Tumour Biol. 2014;35(3):2095–2102.
   PubMedGoogle Scholar
• Staels B, Rubenstrunk A, Noel B, et al. Hepatoprotective effects of the dual peroxisome proliferator-activated receptor alpha/delta agonist, GFT505, in rodent models of nonalcoholic fatty liver disease/nonalcoholic steatohepatitis. Hepatology. 2013;58(6):1941–1952.
   PubMed Web of Science ®Google Scholar
• Odegaard JI, Ricardo-Gonzalez RR, Red Eagle A, et al. Alternative M2 activation of Kupffer cells by PPARdelta ameliorates obesity-induced insulin resistance. Cell Metab. 2008;7(6):496–507.
   PubMed Web of Science ®Google Scholar
• Ratziu V, Harrison SA, Francque S, et al. Elafibranor, an Agonist of the Peroxisome Proliferator-Activated Receptor-alpha and -delta, Induces Resolution of Nonalcoholic Steatohepatitis Without Fibrosis Worsening. Gastroenterology. 2016;150(5):1147–1159.e1145.
   PubMed Web of Science ®Google Scholar
• Phase 3 Study to Evaluate the Efficacy and Safety of Elafibranor Versus Placebo in Patients With Nonalcoholic Steatohepatitis (NASH). (Ed.^(Eds).
   Google Scholar
• Zeng T, Zhang CL, Zhao XL, et al. Pentoxifylline for the treatment of nonalcoholic fatty liver disease: a meta-analysis of randomized double-blind, placebo-controlled studies. Eur J Gastroenterol Hepatol. 2014;26(6):646–653.
   PubMed Web of Science ®Google Scholar
• Harrison SA, Wai-Sun Wong V, Okanoue T, et al. Selonsertib for patients with bridging fibrosis or compensated cirrhosis due to nash: results from randomized Ph III STELLAR trials. J Hepatol. 2020;73(1):26–39. DOI:10.1016/j.jhep.2020.02.027.
   Web of Science ®Google Scholar
• Safety and Efficacy of Selonsertib, Firsocostat, Cilofexor, and Combinations in Participants With Bridging Fibrosis or Compensated Cirrhosis Due to Nonalcoholic Steatohepatitis (NASH). (Ed.^(Eds).
   Google Scholar
• AlAsfoor S, Rohm TV, Bosch AJT, et al. Imatinib reduces non-alcoholic fatty liver disease in obese mice by targeting inflammatory and lipogenic pathways in macrophages and liver. Sci Rep. 2018;8(1):15331.
   PubMedGoogle Scholar