HIF-2α-driven Lipogenesis and Inflammation in Metabolic Dysfunction-associated Steatotic Liver Disease: Role of ATF4 Signaling

BACKGROUND & AIMS: Metabolic dysfunction-associated steatotic liver disease (MASLD) is characterized by an imbalance of lipid metabolism and chronic inflammation. Emerging evidence suggests a role for hypoxia-inducible factor 2α (HIF-2α) in MASLD progression. However, the mechanistic linkage between HIF-2α and steatohepatitis progression remains largely elusive. METHODS: Here, hepatocyte-specific HIF-2α knockout mice were used to investigate the pathophysiological role of HIF-2α in MASLD. Multiple gain- and loss-of-function experiments in primary hepatocytes and established human hepatocyte cell lines were performed to elucidate the molecular mechanisms by which HIF-2α contributes to MASLD progression. RESULTS: Compared with their wild-type littermates, hepatocyte-specific HIF-2α knockout mice exhibited a substantial reduction in high-fat diet-induced hepatic steatosis and inflammatory signaling. Furthermore, HIF-2ɑ deficiency in primary hepatocytes and both L02 and MIHA cell lines markedly inhibited the lipid accumulation, inflammation, and endoplasmic reticulum stress in vitro upon free fatty acids challenge. Mechanistically, HIF-2 directly bound to the promoter region of protein kinase RNA-like ER kinase, leading to the activation of the activating transcription factor 4 signaling under metabolic stress, thereby aggravating lipogenesis while inhibiting lipid oxidation in hepatocytes. CONCLUSIONS: These data indicate that HIF-2α acts as a contributing factor to MASLD progression via activating transcription factor 4 signaling.