G protein-coupled receptor 39 alleviates mitochondrial dysfunction and hepatocyte lipid accumulation via SIRT1/Nrf2 signaling.

Abstract

Objective: Data in the GEO database (GSE63067) showed that G protein-coupled receptor 39 (GPR39) was down-regulated in tissues from patients with non-alcoholic fatty liver disease (NAFLD). It was intended to explore the mechanism of GPR39 in NAFLD.

Methods: HepG2 cells were treated with a mixture of oleic acid and palmitic acid (OA/PA) to mimic NAFLD cell models. The level of GPR39 and the functions of GPR39 on cellular oxidative stress, lipid accumulation, the SIRT1/Nrf2 signaling and mitochondrial dysfunction were assessed. To verify the mediation of the SIRT1 signaling pathway in GPR39 regulation, cells were subjected to SIRT1 inhibitor EX-527 treatment. Afterwards, the abovementioned aspects of cells were all determined.

Results: GPR39 presented a downward trend in response to OA/PA. GPR39 overexpression could suppress oxidative stress, lipid accumulation and activate the SIRT1/Nrf2 signaling. GPR39 overexpression likewise alleviated mitochondrial dysfunction, whereas EX-527 treatment disturbed the effects of GPR39 overexpression on these aspects.

Conclusion: The present study found that GPR39 reduced oxidative stress and maintained mitochondrial homeostasis in a cellular model of NAFLD, a process mediated by SIRT1/Nrf2 signaling.