Background Disorder of lipid metabolism plays an essential role in both initiation and progression of alcoholic fatty liver disease (AFLD), and fatty acid βoxidation is increasingly being considered a crucial factor controlling lipid metabolism. Hif-2α is a member of the Hifs family of nuclear receptors, taking part in regulating hepatic fatty acid β-oxidation. However, its functional role in AFLD and its underlying mechanism remains unclear.
Results Hif-2α was upregulated in EtOH-fed mice and EtOH-induced AML-12 cells. Inhibition or silence of Hif-2α led to the enhancement of fatty acid β-oxidation and BNIP3-dependent mitophagy. Further studies have shown that downregulation of Hif-2α was well established to activate the PPARα/PGC-1α signaling pathway concerned in hepatic fatty acid β-oxidation by mediating BNIP3-dependent mitophagy, and ultimately delaying the progression of AFLD.
Conclusions Hif-2α induces liver steatosis, which promotes the progression of AFLD. Our results preciously developed a novel Hif-2α-BNIP3-dependent mitophagy regulatory pathway interconnected with EtOH-induced lipid accumulation and might be a potential therapeutic target for prevention and treatment of AFLD.