title: Galectin-3 and IL-33/ST2 axis roles and interplay in diet-induced steatohepatitis.
abstract: Immune reactivity and chronic low-grade inflammation (metaflammation) play an important role in the pathogenesis of obesity-associated metabolic disorders, including type 2 diabetes and nonalcoholic fatty liver disease (NAFLD), a spectrum of diseases that include liver steatosis, nonalcoholic steatohepatitis (NASH), fibrosis, and cirrhosis. Increased adiposity and insulin resistance contribute to the progression from hepatic steatosis to NASH and fibrosis through the development of proinflammatory and profibrotic processes in the liver, including increased hepatic infiltration of innate and adaptive immune cells, altered balance of cytokines and chemokines, increased reactive oxygen species generation and hepatocellular death. Experimental models of dietary-induced NAFLD/NASH in mice on different genetic backgrounds or knockout mice with different immune reactivity are used for elucidating the pathogenesis of NASH and liver fibrosis. Galectin-3 (Gal-3), a unique chimera-type β-galactoside-binding protein of the galectin family has a regulatory role in immunometabolism and fibrogenesis. Mice deficient in Gal-3 develop pronounced adiposity, hyperglycemia and hepatic steatosis, as well as attenuated liver inflammation and fibrosis when fed an obesogenic high-fat diet. Interleukin (IL)-33, a member of the IL-1 cytokine family, mediates its effects through the ST receptor, which is present on immune and nonimmune cells and participates in immunometabolic and fibrotic disorders. Recent evidence, including our own data, suggests a protective role for the IL-33/IL-33R (ST2) signaling pathway in obesity, adipose tissue inflammation and atherosclerosis, but a profibrotic role in NASH development. The link between Gal-3 and soluble ST2 in myocardial fibrosis and heart failure progression has been demonstrated and we have recently shown that Gal-3 and the IL-33/ST2 pathway interact and both have a profibrotic role in diet-induced NASH. This review discusses the current evidence on the roles of Gal-3 and the IL-33/ST2 pathway and their interplay in obesity-associated hepatic inflammation and fibrogenesis that may be of interest in the development of therapeutic interventions to prevent and/or reverse obesity-associated hepatic inflammation and fibrosis.
authors.affiliation: Nada Pejnovic, Ilija Jeftic, Nemanja Jovicic, Nebojsa Arsenijevic, Miodrag L Lukic, Center for Molecular Medicine and Stem Cell Research, Faculty of Medical Sciences, University of Kragujevac, 34000 Kragujevac, Serbia.
authors.forename: Nada
authors.initials: N
authors.lastname: Pejnovic
authors.affiliation: Nada Pejnovic, Ilija Jeftic, Nemanja Jovicic, Nebojsa Arsenijevic, Miodrag L Lukic, Center for Molecular Medicine and Stem Cell Research, Faculty of Medical Sciences, University of Kragujevac, 34000 Kragujevac, Serbia.
authors.forename: Ilija
authors.initials: I
authors.lastname: Jeftic
authors.affiliation: Nada Pejnovic, Ilija Jeftic, Nemanja Jovicic, Nebojsa Arsenijevic, Miodrag L Lukic, Center for Molecular Medicine and Stem Cell Research, Faculty of Medical Sciences, University of Kragujevac, 34000 Kragujevac, Serbia.
authors.forename: Nemanja
authors.initials: N
authors.lastname: Jovicic
authors.affiliation: Nada Pejnovic, Ilija Jeftic, Nemanja Jovicic, Nebojsa Arsenijevic, Miodrag L Lukic, Center for Molecular Medicine and Stem Cell Research, Faculty of Medical Sciences, University of Kragujevac, 34000 Kragujevac, Serbia.
authors.forename: Nebojsa
authors.initials: N
authors.lastname: Arsenijevic
authors.affiliation: Nada Pejnovic, Ilija Jeftic, Nemanja Jovicic, Nebojsa Arsenijevic, Miodrag L Lukic, Center for Molecular Medicine and Stem Cell Research, Faculty of Medical Sciences, University of Kragujevac, 34000 Kragujevac, Serbia.
authors.forename: Miodrag L
authors.initials: ML
authors.lastname: Lukic
mesh_terms: D000818:Animals; D001798:Blood Proteins; D059305:Diet, High-Fat / Q000009:adverse effects*; D004195:Disease Models, Animal; D018450:Disease Progression; D037502:Galectin 3 / Q000378:metabolism*; D037161:Galectins; D006801:Humans; D000072179:Interleukin-1 Receptor-Like 1 Protein / Q000378:metabolism*; D000067596:Interleukin-33 / Q000378:metabolism*; D008099:Liver / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D008103:Liver Cirrhosis / Q000209:etiology / Q000378:metabolism; D065626:Non-alcoholic Fatty Liver Disease / Q000175:diagnosis / Q000209:etiology* / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D001798:Blood Proteins; D037502:Galectin 3; D037161:Galectins; C079241:IL1RL1 protein, human; C506536:IL33 protein, human; D000072179:Interleukin-1 Receptor-Like 1 Protein; D000067596:Interleukin-33; C428445:LGALS3 protein, human
keywords: Galectin-3; Interleukin-33; Liver fibrosis; Nonalcoholic steatohepatitis; ST2