Hypoxia‐induced lipid accumulation involves a HIF‐α independent, oxidative stress‐mediated regulation of FGF‐21 in HepG2 cells

Abstract

Fibroblast growth factor 21 (FGF‐21) has emerged as an important metabolic regulator of glucose and lipid metabolism. Previous studies have indicated that FGF‐21 regulates lipolysis in the adipose tissue, and increases fatty acid oxidation in the liver. Although hypoxia has been attributed to lipid metabolic dysfunction in several tissues, it is not known whether hypoxia plays a role in FGF‐21 regulation. In the present study, HepG2 cells were used to determine the role of FGF‐21 regulation in cellular triglyceride accumulation under physical and chemical hypoxia. Incubation of HepG2 cells with a chemical hypoxia inducer, CoCl2, or exposing the cells to 1% O2, significantly increased hypoxia‐inducible factor 1α protein accumulation and the target gene, glucose transport 1, expression, and dramatically reduced cellular FGF‐21 mRNA and secreted FGF‐21 protein levels along with a significant increase in cellular triglyceride content. Chemical hypoxia also induced a significant reduction in PPARα/γ mRNA levels, which have been shown to regulate FGF‐21 expression in hepatocytes and adipocytes. Knocking down HIF‐1α or HIF‐2α using specific siRNAs neither restored CoCl2‐reduced FGF‐21 expression, nor reduced triglyceride accumulation, indicating that HIF‐α is not responsible for CoCl2‐induced FGF‐21 reduction and fat accumulation. However, addition of N‐acetyl cysteine completely restored CoCl2‐induced reduction in FGF‐21, and attenuated the fat accumulation, indicating the role of oxidative stress in hypoxia mediated FGF21 regulation and lipid metabolism. The results suggest that hypoxia regulates FGF‐21 and cellular fat metabolism through a HIF‐α independent, but oxidative stress‐mediated pathway.