Netrin-1 attenuates hepatic steatosis via UNC5b/PPARγ-mediated suppression of inflammation and ER stress
- Authors
- Choi, S.W.; Oh, H.; Park, S.Y.; Cho, W.; Abd, El-Aty A.M.; Baygutalp, N.K.; Jeong, J.H.; Jung, T.W.
- Issue Date
- Dec-2022
- Publisher
- Elsevier Inc.
- Keywords
- Autophagy; ER stress; Inflammation; Metabolic-associated fatty liver disease; Netrin-1; PPARγ
- Citation
- Life Sciences, v.311
- Journal Title
- Life Sciences
- Volume
- 311
- URI
- https://scholarworks.bwise.kr/cau/handle/2019.sw.cau/70346
- DOI
- 10.1016/j.lfs.2022.121149
- ISSN
- 0024-3205
1879-0631
- Abstract
- Aims: The current study investigated whether netrin-1 can attenuate hepatic steatosis through PPARγ/autophagy-mediated suppression of inflammation and endoplasmic reticulum (ER) stress in experimental animal models. Main methods: Hepatic steatosis was induced by a high-fat diet in experimental mice. Recombinant mouse netrin-1 was administered via the tail vein (1 μg/mouse, once every two days). Serum inflammatory cytokines and hepatic inflammatory and ER stress markers were determined in mice using ELISA and western blotting protocol. Key findings: We found that netrin-1 expression was significantly increased (P < 0.05) in cultured macrophages treated with supernatants of subcutaneous adipocytes in the presence of palmitate and subcutaneous fat of obese mice. Recombinant netrin-1 treatment promoted PPARγ expression and autophagy, thereby attenuating inflammation and ER stress, lipid accumulation, and the expression of lipogenic proteins in mouse primary hepatocytes. High-fat diet (HFD) treatment increased hepatic inflammation and ER stress, causing hepatic steatosis in experimental mice. However, administration of netrin-1 reversed the effects of HFD on hepatic ER stress and lipid deposition. Significance: These results suggest that subcutaneous adipose macrophage-derived netrin-1 ameliorates inflammation and ER stress in the liver, which in turn alleviates hepatic steatosis by enhancing basal PPARγ/autophagy-dependent signaling. The current study sheds light on the pathogenesis of hepatic steatosis in obesity and provides a promising therapeutic approach for treating metabolic-associated fatty liver disease (MAFLD). © 2022 Elsevier Inc.
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