The Mechanism by which HIF-2a Promotes MASLD

Metabolic dysfunction-associated steatotic liver disease (MASLD) is characterized by imbalance of lipid metabolism and autoimmune inflammation. The relationship between Hypoxia-inducible Factor 2a (HIF-2a) and the progression of MASLD has been well-documented. However, the mechanistic linkage between HIF-2a and steatohepatitis progression remains largely elusive. Here, hepatocyte-specific HIF-2a knockout mice were used to identify underlying pathophysiological relevance in MASLD. Through multiple gain- and loss-of-function experiments in primary hepatocytes and established human hepatocyte cell lines to investigate the molecular mechanism of HIF-2a in MASLD progression. Compared to their wild-type littermates, hepatocyte-specific HIF-2a knockout mice exhibited a substantial reduction in hepatic steatosis and inflammatory pathway induced by high fat diet (HFD). Furthermore, the HIF-2? deficiency in primary hepatocytes and both L02 and MIHA cell lines markedly inhibited the lipid accumulation, inflammation and endoplasmic reticulum stress in vitro under FFAs challenge. Mechanistically, HIF-2 directly bound to the promoter region of protein kinase RNA-like ER kinase (PERK), leading to the activation of the activating transcription Factor 4 (ATF4) signaling under metabolic stress, thereby aggravating lipogenesis while inhibiting lipid oxidation in hepatocytes.These data indicate that HIF-2a acts as a contributing factor to MASLD progression via ATF4 signaling. Overall design: To investigate the role of HIF-2a in the progression of MASLD, we performed RNA-seq on liver tissues of HIF-2a-deficient mice subjected to a 16-week HFD