Hypoxia ameliorates high-fat-diet-induced hepatic lipid accumulation by modulating the HIF2α/PP4C signaling

Hepatic lipid accumulation is a hallmark of metabolically associated fatty liver disease (MAFLD), which contributes to the progression of cirrhosis and even hepatoma. However, the underlying mechanisms remain poorly understood. Protein phosphatase 4C (PP4C) is an important enzyme that exists widely in the body and participates in cell metabolism. Hypoxia can affect the development of metabolic diseases. In this study, we investigated the role of PP4C in hepatic lipid metabolism under hypoxia in vivo and in vitro. Hypoxia-inducible factor 2α (HIF2α), PP4C, phosphorylated AU-rich element RNA-binding factor 1(pAUF1), acetyl-CoA carboxylase 1 (ACC1), and carnitine palmitoyl transferase-1 (CPT1) were analyzed via western blotting and immunofluorescence. The mechanism by which PP4C affects hepatic lipid accumulation under hypoxia was evaluated in stable transfected cell lines. Compared with those in the 2200 m HFD group, body weight, triglyceride (TG), total cholesterol (TC), amino alanine transferase (ALT), aspartate transaminase (AST), and lipid accumulation were lower in the 4500 m HFD group (P < 0.05). Compared with those in the 4500 m ND group, ACC1 and PP4C levels were lower than in the 4500 m HFD group, but HIF2α, pAUF1, and CPT1 levels were greater (P < 0.05). Knockdown of HIF2α prevented the hypoxia-induced reduction of PP4C, confirming the regulatory role of the HIF2α-PP4C axis in hepatic lipid metabolism. PP4C could affect the phosphorylation and expression localization of AU-rich element RNA-binding factor 1 (AUF1). PP4C enhanced lipid accumulation by reducing pAUF1, while the knockdown of PP4C had the opposite effect; pAUF1 had no change. Compared with those in the control group, ACC1 levels were decreased and CPT1 levels were increased in the AUF1 overexpression group, whereas ACC1 and CPT1 levels were not altered in the AUF1 knockdown group (P < 0.05). In conclusion, hypoxia might improve lipid accumulation by downregulating PP4C via HIF2a. PP4C is involved in hepatic lipid metabolism by regulating AUF1 phosphorylation under different oxygen concentrations. PP4C might be a promising target for treating hepatic lipid accumulation.