Galectin-3 Ablation Enhances Liver Steatosis, but Attenuates Inflammation and IL-33-Dependent Fibrosis in Obesogenic Mouse Model of Nonalcoholic Steatohepatitis

Ilija Jeftic, Nemanja Jovicic, Jelena Pantic, Nebojsa Arsenijevic, Miodrag L. Lukic, Nada Pejnovic

The importance of Galectin-3 (Gal-3) in obesity-associated liver pathology is incompletely defined. In order 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 obesogenic high-fat diet (HFD, 60% kcal fat) or standard chow diet for 12 and 24 weeks. 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 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 higher number of hepatocytes that strongly expressed IL-33 and hepatic CD11b(+)IL-13(+) cells, increased levels of IL-33 and IL-13 and upregulated IL-33, ST2 and IL-13 mRNA in liver compared to LGALS3(-/-) mice. IL-33 failed to induce ST2 upregulation and IL-13 production by LGALS3(-/-) peritoneal macrophages in vitro. In vivo administration of IL-33 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.