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Molecular Medicine

, Volume 21, Issue 1, pp 453–465 | Cite as

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
Research Article

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+Ly6Chi 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.

Notes

Acknowledgments

We thank Ivan Jovanovic, Gordana Radosavljevic and Ivana Stojanovic for collegial help and Aleksandar Ilic, Katerina Martinova, Sandra Nikolic (Center for Molecular Medicine, Faculty of Medical Sciences, University of Kragujevac) and Zoran Mitrovic (Institute of Pathology, Faculty of Medical Sciences, University of Kragujevac) for technical assistance. This work was supported by grants from the Serbian Ministry of Science and Technological Development (175071 and 175069) (Belgrade, Serbia), Swiss Science Foundation (SCOPES, IZ73Z0_152407) and junior faculty grants (JP 02-14, JP 03-14) Faculty of Medical Sciences, Kragujevac, Serbia.

Supplementary material

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Authors and Affiliations

  • Ilija Jeftic
    • 1
    • 2
  • Nemanja Jovicic
    • 1
    • 3
  • Jelena Pantic
    • 1
  • Nebojsa Arsenijevic
    • 1
  • Miodrag L. Lukic
    • 1
  • Nada Pejnovic
    • 1
    • 2
  1. 1.Center for Molecular Medicine and Stem Cell Research, Faculty of Medical SciencesUniversity of KragujevacKragujevacSerbia
  2. 2.Institute of Pathophysiology, Faculty of Medical SciencesUniversity of KragujevacKragujevacSerbia
  3. 3.Institute of Histology, Faculty of Medical SciencesUniversity of KragujevacKragujevacSerbia

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