Netrin-1 attenuates hepatic steatosis<i> via</i> UNC5b/PPAR?-mediated suppression of inflammation and ER stress

Aims: The current study investigated whether netrin-1 can attenuate hepatic steatosis through PPAR gamma/auto-phagy-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 mu g/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 PPAR gamma 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 inflam-mation and ER stress in the liver, which in turn alleviates hepatic steatosis by enhancing basal PPAR gamma/auto-phagy-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).

Dergi

LIFE SCIENCES

Yıl

2022

Cilt

311

ISSN

0024-3205

eISSN

1879-0631

DOI

10.1016/j.lfs.2022.121149

WoS UID

WOS:000954467600004