title: Galectin-3 Ablation Enhances Liver Steatosis, but Attenuates Inflammation and IL-33-Dependent Fibrosis in Obesogenic Mouse Model of Nonalcoholic Steatohepatitis.
abstract: The importance of Galectin-3 (Gal-3) in obesity-associated liver pathology is incompletely defined. To dissect the role of Gal-3 in fibrotic nonalcoholic steatohepatitis (NASH), Gal-3-deficient (LGALS3(-/-)) and wild-type (LGALS3(+/+)) C57Bl/6 mice were placed on an obesogenic high fat diet (HFD, 60% kcal fat) or standard chow diet for 12 and 24 wks. Compared to WT mice, HFD-fed LGALS3(-/-) mice developed, in addition to increased visceral adiposity and diabetes, marked liver steatosis, which was accompanied with higher expression of hepatic PPAR-γ, Cd36, Abca-1 and FAS. However, as opposed to LGALS3(-/-) mice, hepatocellular damage, inflammation and fibrosis were more extensive in WT mice which had an elevated number of mature myeloid dendritic cells, proinflammatory CD11b(+)Ly6C(hi) monocytes/macrophages in liver, peripheral blood and bone marrow, and increased hepatic CCL2, F4/80, CD11c, TLR4, CD14, NLRP3 inflammasome, IL-1β and NADPH-oxidase enzymes mRNA expression. Thus, obesity-driven greater steatosis was uncoupled with attenuated fibrotic NASH in Gal-3-deficient mice. HFD-fed WT mice had a higher number of hepatocytes that strongly expressed IL-33 and hepatic CD11b(+)IL-13(+) cells, increased levels of IL-33 and IL-13 and up-regulated IL-33, ST2 and IL-13 mRNA in liver compared with LGALS3(-/-) mice. IL-33 failed to induce ST2 upregulation and IL-13 production by LGALS3(-/-) peritoneal macrophages in vitro. Administration of IL-33 in vivo enhanced liver fibrosis in HFD-fed mice in both genotypes, albeit to a significantly lower extent in LGALS3(-/-) mice, which was associated with less numerous hepatic IL-13-expressing CD11b(+) cells. The present study provides evidence of a novel role for Gal-3 in regulating IL-33-dependent liver fibrosis.
authors.affiliation: Center for Molecular Medicine and Stem Cell Research, Faculty of Medical Sciences, University of Kragujevac, Kragujevac, Serbia.|Institute of Pathophysiology, Faculty of Medical Sciences, University of Kragujevac, Kragujevac, Serbia.
authors.forename: Ilija
authors.initials: I
authors.lastname: Jeftic
authors.affiliation: Center for Molecular Medicine and Stem Cell Research, Faculty of Medical Sciences, University of Kragujevac, Kragujevac, Serbia.|Institute of Histology, Faculty of Medical Sciences, University of Kragujevac, Kragujevac, Serbia.
authors.forename: Nemanja
authors.initials: N
authors.lastname: Jovicic
authors.affiliation: Center for Molecular Medicine and Stem Cell Research, Faculty of Medical Sciences, University of Kragujevac, Kragujevac, Serbia.
authors.forename: Jelena
authors.initials: J
authors.lastname: Pantic
authors.affiliation: Center for Molecular Medicine and Stem Cell Research, Faculty of Medical Sciences, University of Kragujevac, Kragujevac, Serbia.
authors.forename: Nebojsa
authors.initials: N
authors.lastname: Arsenijevic
authors.affiliation: Center for Molecular Medicine and Stem Cell Research, Faculty of Medical Sciences, University of Kragujevac, Kragujevac, Serbia.
authors.forename: Miodrag L
authors.initials: ML
authors.lastname: Lukic
authors.affiliation: Center for Molecular Medicine and Stem Cell Research, Faculty of Medical Sciences, University of Kragujevac, Kragujevac, Serbia.|Institute of Pathophysiology, Faculty of Medical Sciences, University of Kragujevac, Kragujevac, Serbia.
authors.forename: Nada
authors.initials: N
authors.lastname: Pejnovic
mesh_terms: D000818:Animals; D059305:Diet, High-Fat; D004195:Disease Models, Animal; D005234:Fatty Liver / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D005355:Fibrosis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D037502:Galectin 3 / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000473:pathology; D000067596:Interleukin-33 / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D008099:Liver / Q000378:metabolism / Q000473:pathology; D051379:Mice; D065626:Non-alcoholic Fatty Liver Disease / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D009765:Obesity / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics
chemical_list: D037502:Galectin 3; C506535:Il33 protein, mouse; D000067596:Interleukin-33; C485095:Lgals3 protein, mouse; D014409:Tumor Necrosis Factor-alpha