Spotlight on liver macrophages for halting injury and progression in nonalcoholic fatty liver disease

References

• Younossi Z, Anstee QM, Marietti M, et al. Global burden of NAFLD and NASH: trends, predictions, risk factors and prevention. Nat Rev Gastroenterol Hepatol. 2018 Jan;15(1):11–20.
   PubMed Web of Science ®Google Scholar
• Angulo P, Kleiner DE, Dam-Larsen S, et al. Liver fibrosis, but no other histologic features, is associated with long-term outcomes of patients with nonalcoholic fatty liver Disease. Gastroenterology. 2015 Aug;149(2):389–97e10.
   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
• Kazankov K, Jorgensen SMD, Thomsen KL, et al. The role of macrophages in nonalcoholic fatty liver disease and nonalcoholic steatohepatitis. Nature Reviews. Gastroenterology & Hepatology. 2019 Mar;16(3):145–159.
   PubMed Web of Science ®Google Scholar
• Peiseler M, Schwabe R, Hampe J, et al. Immune mechanisms linking metabolic injury to inflammation and fibrosis in fatty liver disease - novel insights into cellular communication circuits. J Hepatol 2022; 77(4):1136–1160
   PubMedGoogle Scholar
• Wallace SJ, Tacke F, Schwabe RF, et al. Understanding the cellular interactome of non-alcoholic fatty liver disease. JHEP Reports: Innovation in Hepatology. 2022 Aug;4(8):100524.
   PubMedGoogle Scholar
• Fuchs CD, Trauner M. Role of bile acids and their receptors in gastrointestinal and hepatic pathophysiology. Nature Reviews. Gastroenterology & Hepatology. 2022 Jul;19(7):432–450.
   PubMed Web of Science ®Google Scholar
• Pejnovic N, Jeftic I, Jovicic N, et al. Galectin-3 and IL-33/ST2 axis roles and interplay in diet-induced steatohepatitis. World Journal of Gastroenterology. 2016 Nov 28;22(44):9706–9717.
   PubMed Web of Science ®Google Scholar
• MacParland SA, Liu JC, Ma X-Z, et al. Single cell RNA sequencing of human liver reveals distinct intrahepatic macrophage populations. Nat Commun. 2018 Oct 22;9(1):4383.
   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. Gut. 2020 Mar;69(3):551–563.
   PubMed Web of Science ®Google Scholar
• Barreby E, Chen P, Aouadi M. Macrophage functional diversity in NAFLD - more than inflammation. Nat Rev Endocrinol 2022; 18(8):461–472.
   PubMed Web of Science ®Google Scholar
• Morgantini C, Jager J, Li X, et al. Liver macrophages regulate systemic metabolism through non-inflammatory factors nat metab. Nature Metabolism. 2019 Apr;1(4):445–459.
   PubMedGoogle Scholar
• Deshmane SL, Kremlev S, Amini S, et al. Monocyte chemoattractant protein-1 (MCP-1): an overview. Journal of Interferon & Cytokine Research: the Official Journal of the International Society for Interferon and Cytokine Research. 2009 Jun;29(6):313–326.
   PubMed Web of Science ®Google Scholar
• Miura K, Yang L, van Rooijen N, et al. Toll-like receptor 2 and palmitic acid cooperatively contribute to the development of nonalcoholic steatohepatitis through inflammasome activation in mice. Hepatology (Baltimore, MD). 2013;57(2):577–589.
   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 (Baltimore, MD). 2018 Apr;67(4):1270–1283.
   PubMed Web of Science ®Google Scholar
• Tacke F. Targeting hepatic macrophages to treat liver diseases. Journal of Hepatology. 2017 Jun;66(6):1300–1312.
   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. Digestive and Liver Disease: Official Journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver. 2013;45(7):543–551.
   PubMedGoogle Scholar
• Sookoian S, Salatino A, Castano GO, et al. Intrahepatic bacterial metataxonomic signature in non-alcoholic fatty liver disease. Gut. 2020 Aug;69(8):1483–1491.
   PubMed Web of Science ®Google Scholar
• Kawaratani H, Tsujimoto T, Kitazawa T, et al. Innate immune reactivity of the liver in rats fed a choline-deficient L-amino-acid-defined diet. World Journal of Gastroenterology. 2008;14(43):6655–6661.
   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. Journal of Hepatology. 2012;57(1):141–149.
   PubMed Web of Science ®Google Scholar
• Budick-Harmelin N, Dudas J, Demuth J, et al. Triglycerides potentiate the inflammatory response in rat Kupffer cells. Antioxidants & Redox Signaling. 2008;10(12):2009–2022.
   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. Journal of Hepatology. 2007;47(4):571–579.
   PubMed Web of Science ®Google Scholar
• Ye D, Li FYL, Lam KSL, et al. Toll-like receptor-4 mediates obesity-induced non-alcoholic steatohepatitis through activation of X-box binding protein-1 in mice. Gut. 2012;61(7):1058–1067.
   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 (Baltimore, MD). 2010;52(2):774–788.
   PubMed Web of Science ®Google Scholar
• Lee JY, Sohn KH, Rhee SH, et al. Saturated fatty acids, but not unsaturated fatty acids, induce the expression of cyclooxygenase-2 mediated through Toll-like receptor 4. JBiolChem. 2001;276(20):16683–16689.
   PubMed Web of Science ®Google Scholar
• Canbay A, Feldstein AE, Higuchi H, et al. Kupffer cell engulfment of apoptotic bodies stimulates death ligand and cytokine expression. Hepatology (Baltimore, MD). 2003;38(5):1188–1198.
   PubMed Web of Science ®Google Scholar
• Jindal A, Bruzzi S, Sutti S, et al. Fat-laden macrophages modulate lobular inflammation in nonalcoholic steatohepatitis (NASH). Experimental and Molecular Pathology. 2015 Aug;99(1):155–162.
   PubMed Web of Science ®Google Scholar
• Cannito S, Morello E, Bocca C, et al. Microvesicles released from fat-laden cells promote activation of hepatocellular NLRP3 inflammasome: a pro-inflammatory link between lipotoxicity and non-alcoholic steatohepatitis. PloS One. 2017;12(3):e0172575.
   PubMed Web of Science ®Google Scholar
• Carter-Kent C, Zein NN, Feldstein AE. Cytokines in the pathogenesis of fatty liver and disease progression to steatohepatitis: implications for treatment. The American Journal of Gastroenterology. 2008;103(4):1036–1042.
   PubMed Web of Science ®Google Scholar
• Huang W, Metlakunta A, Dedousis N, et al. Depletion of liver Kupffer cells prevents the development of diet-induced hepatic steatosis and insulin resistance. Diabetes. 2010;59(2):347–357.
   PubMed Web of Science ®Google Scholar
• Lanthier N, Molendi-Coste O, Horsmans Y, et al. Kupffer cell activation is a causal factor for hepatic insulin resistance. American Journal of Physiology. Gastrointestinal and Liver Physiology. 2010;298(1):G107–G16.
   PubMed Web of Science ®Google Scholar
• Pradere J-P, Kluwe J, De Minicis S, et al. Hepatic macrophages but not dendritic cells contribute to liver fibrosis by promoting the survival of activated hepatic stellate cells in mice. Hepatology (Baltimore, MD). 2013 Oct;58(4):1461–1473.
   PubMed Web of Science ®Google Scholar
• Stienstra R, Mandard S, Patsouris D, et al. Peroxisome proliferator-activated receptor alpha protects against obesity-induced hepatic inflammation. Endocrinology. 2007 Jun;148(6):2753–2763.
   PubMed Web of Science ®Google Scholar
• Tencerova M, Aouadi M, Vangala P, et al. Activated Kupffer cells inhibit insulin sensitivity in obese mice. FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology. 2015 Jul;29(7):2959–2969.
   PubMed Web of Science ®Google Scholar
• Chen L, Ye H, Zhao X, et al. Selective depletion of hepatic Kupffer cells significantly alleviated hepatosteatosis and intrahepatic inflammation induced by high fat diet. Hepato-gastroenterology. 2012;59(116):1208–1212.
   PubMedGoogle Scholar
• Kodama Y, Kisseleva T, Iwaisako K, et al. c-Jun N-terminal kinase-1 from hematopoietic cells mediates progression from hepatic steatosis to steatohepatitis and fibrosis in mice. Gastroenterology. 2009;137(4):1467–1477.
   PubMed Web of Science ®Google Scholar
• Malehmir M, Pfister D, Gallage S, et al. Platelet GPIbα is a mediator and potential interventional target for NASH and subsequent liver cancer. Nature Medicine. 2019 Apr;25(4):641–655.
   PubMed Web of Science ®Google Scholar
• Fuentes L, Roszer T, Ricote M. Inflammatory mediators and insulin resistance in obesity: role of nuclear receptor signaling in macrophages. Mediators of Inflammation. 2010;2010:219583.
   PubMed Web of Science ®Google Scholar
• Bugianesi E, Gastaldelli A, Vanni E, et al. Insulin resistance in non-diabetic patients with non-alcoholic fatty liver disease: sites and mechanisms. Diabetologia. 2005;48(4):634–642.
   PubMed Web of Science ®Google Scholar
• Kazankov K, Bojsen-Moller KN, Moller HJ, et al. Macrophage activation marker sCD163 is associated with liver injury and hepatic insulin resistance in obese patients before and after Roux-en-Y gastric bypass. Physiological Reports. 2022 Jan;10(2):e15157.
   PubMed Web of Science ®Google Scholar
• Rosso C, Kazankov K, Younes R, et al. Crosstalk between adipose tissue insulin resistance and liver macrophages in non-alcoholic fatty liver disease. J Hepatol. 2019 Nov;71(5):1012–1021.
   PubMed Web of Science ®Google Scholar
• Wang J, Leclercq I, Brymora JM, et al. Kupffer cells mediate leptin-induced liver fibrosis. Gastroenterology. 2009;137(2):713–723.
   PubMed Web of Science ®Google Scholar
• Polyzos SA, Kountouras J, Mantzoros CS. Leptin in nonalcoholic fatty liver disease: a narrative review. Metabolism: Clinical and Experimental. 2015 Jan;64(1):60–78.
   PubMed Web of Science ®Google Scholar
• Chatterjee S, Ganini D, Tokar EJ, et al. Leptin is key to peroxynitrite-mediated oxidative stress and Kupffer cell activation in experimental non-alcoholic steatohepatitis. Journal of Hepatology. 2013;58(4):778–784.
   PubMed Web of Science ®Google Scholar
• Gatselis NK, Ntaios G, Makaritsis K, et al. Adiponectin: a key playmaker adipocytokine in non-alcoholic fatty liver disease. Clinical and Experimental Medicine. 2014;14(2):121–131.
   PubMed Web of Science ®Google Scholar
• Tsatsanis C, Zacharioudaki V, Androulidaki A, et al. Adiponectin induces TNF-alpha and IL-6 in macrophages and promotes tolerance to itself and other pro-inflammatory stimuli. Biochemical and Biophysical Research Communications. 2005;335(4):1254–1263.
   PubMed Web of Science ®Google Scholar
• Moller HJ. Soluble CD163. Scandinavian Journal of Clinical and Laboratory Investigation. 2012 Feb;72(1):1–13.
   PubMed Web of Science ®Google Scholar
• Rodgaard-Hansen S, Rafique A, Christensen PA, et al. A soluble form of the macrophage-related mannose receptor (MR/CD206) is present in human serum and elevated in critical illness. Clinical Chemistry and Laboratory Medicine. 2014 Mar;52(3):453–461.
   PubMed Web of Science ®Google Scholar
• Indira Chandran V, Wernberg CW, Lauridsen MM, et al. Circulating TREM2 as a noninvasive diagnostic biomarker for NASH in patients with elevated liver stiffness Hepatology. 2022 Jun 16
   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 (Baltimore, MD). 2018 May;67(5):1754–1767.
   PubMed Web of Science ®Google Scholar
• Ratziu V, Sanyal A, Harrison SA, et al. Cenicriviroc Treatment for Adults With Nonalcoholic Steatohepatitis and Fibrosis: final Analysis of the Phase 2b CENTAUR Study. Hepatology (Baltimore, MD). 2020 Sep;72(3):892–905.
   PubMed Web of Science ®Google Scholar
• Anstee QM, Neuschwander-Tetri BA, Wong VW-S, et al. Cenicriviroc for the treatment of liver fibrosis in adults with nonalcoholic steatohepatitis: aurora Phase 3 study design. Contemporary Clinical Trials. 2020 Feb;89:105922.
   PubMed Web of Science ®Google Scholar
• https://clinicaltrials.gov/ct2/show/NCT03028740
   Google Scholar
• MacKinnon AC, Farnworth SL, Hodkinson PS, et al. Regulation of alternative macrophage activation by galectin-3. J Immunol. 2008 Feb 15;180(4):2650–2658.
   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. Journal of Immunology (Baltimore, MD: 1950). 1982 May;128(5):2281–2286.
   PubMed Web of Science ®Google Scholar
• Traber PG, Zomer E. Therapy of experimental NASH and fibrosis with galectin inhibitors. PloS one. 2013;8(12):e83481.
   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 Apr;158(5):1334–45e5.
   PubMed Web of Science ®Google Scholar
• https://clinicaltrials.gov/ct2/show/NCT02421094UNLoMCg
   Google Scholar
• Bird TG, Lu W-Y, Boulter L, et al. Bone marrow injection stimulates hepatic ductular reactions in the absence of injury via macrophage-mediated TWEAK signaling. Science. 2013 Apr 16;110(16):6542–6547.
   Google Scholar
• Moroni F, Dwyer BJ, Graham C, et al. Safety profile of autologous macrophage therapy for liver cirrhosis. Nature Medicine. 2019 Oct;25(10):1560–1565.
   PubMed Web of Science ®Google Scholar
• https://www.isrctn.com/ISRCTN10368050
   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 Mar 14;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 Dec 14;394(10215):2184–2196.
   PubMed Web of Science ®Google Scholar
• Mantovani A, Petracca G, Beatrice G, et al. Glucagon-like peptide-1 receptor agonists for treatment of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis: an updated meta-analysis of randomized controlled trials metabolite Metabolites . 2021; 11(2 1–14)
   Web of Science ®Google Scholar
• Wang X-C, Gusdon AM, Liu H, et al. Effects of glucagon-like peptide-1 receptor agonists on non-alcoholic fatty liver disease and inflammation. World Journal of Gastroenterology. 2014 Oct 28;20(40):14821–14830.
   PubMed Web of Science ®Google Scholar
• Newsome PN, Buchholtz K, Cusi K, et al. A placebo-controlled trial of subcutaneous semaglutide in nonalcoholic steatohepatitis. N Engl J Med. 2021 Mar 25;384(12):1113–1124.
   PubMed Web of Science ®Google Scholar
• https://ir.genfit.com/news-releases/news-release-details/genfit-announces-results-interim-analysis-resolve-it-phase-3/
   Google Scholar
• Malik A, Nadeem M, Malik MI. Efficacy of elafibranor in patients with liver abnormalities especially non-alcoholic steatohepatitis: a systematic review and meta-analysis. Clinical Journal of Gastroenterology. 2021 Dec;14(6):1579–1586.
   PubMed Web of Science ®Google Scholar
• Francque SM, Bedossa P, Ratziu V, et al. A Randomized, Controlled Trial of the Pan-PPAR Agonist Lanifibranor in NASH. The New England Journal of Medicine. 2021 Oct 21;385(17):1547–1558.
   PubMed Web of Science ®Google Scholar
• Harrison SA, Wong VW-S, Okanoue T, et al. Selonsertib for patients with bridging fibrosis or compensated cirrhosis due to NASH: results from randomized phase III STELLAR trials. Journal of Hepatology. 2020 Jul;73(1):26–39.
   PubMed Web of Science ®Google Scholar
• Kazankov K, Barrera F, Møller HJ, et al. The macrophage activation marker sCD163 is associated with morphological disease stages in patients with non-alcoholic fatty liver disease. Liver International: Official Journal of the International Association for the Study of the Liver. 2016;36(10):1549–1557.
   PubMed Web of Science ®Google Scholar
• Kazankov K, Tordjman J, Møller HJ, et al. Macrophage activation marker soluble CD163 and non-alcoholic fatty liver disease in morbidly obese patients undergoing bariatric surgery. Journal of Gastroenterology and Hepatology. 2015;30(8):1293–1300.
   PubMed Web of Science ®Google Scholar
• Mueller JL, Feeney ER, Zheng H, et al. Circulating Soluble CD163 is Associated with Steatohepatitis and Advanced Fibrosis in Nonalcoholic Fatty Liver Disease. Clinical and Translational Gastroenterology. 2015 Oct 8;6(10):e114.
   PubMedGoogle Scholar
• Kazankov K, Rosso C, Younes R, et al. Macrophage markers do not add to the prediction of liver fibrosis by transient elastography in patients with metabolic associated fatty liver disease frontiers in medicine. 2020
   Google Scholar
• Kazankov K, Alisi A, Moller HJ, et al. Macrophage Markers Are Poorly Associated With Liver Histology in Children With Nonalcoholic Fatty Liver Disease. Journal of Pediatric Gastroenterology and Nutrition. 2018 Nov;67(5):635–642.
   PubMed Web of Science ®Google Scholar
• Kazankov K, Møller 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. Pediatric Obesity. 2015;10(3):226–233.
   PubMed Web of Science ®Google Scholar
• Rødgaard-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 Nov;77(7):498–504.
   PubMed Web of Science ®Google Scholar
• Fjeldborg K, Pedersen SB, Møller HJ, et al. Intrahepatic fat content correlates with soluble CD163 in relation to weight loss induced by Roux-en-Y gastric bypass. Obesity (Silver Spring, MD). 2015;23(1):154–161.
   PubMed Web of Science ®Google Scholar
• Corey KE, Wilson LA, Altinbas A, et al. Relationship between resolution of non-alcoholic steatohepatitis and changes in lipoprotein sub-fractions: a post-hoc analysis of the PIVENS trial. Alimentary Pharmacology & Therapeutics. 2019;49(9):1205–1213.
   PubMed Web of Science ®Google Scholar
• Heebøll S, Kreuzfeldt M, Hamilton-Dutoit S, et al. Placebo-controlled, randomised clinical trial: high-dose resveratrol treatment for non-alcoholic fatty liver disease. Scand J Gastroenterol. 20162016/04/02;51(4):456–464.
   PubMed Web of Science ®Google Scholar