Hepatic HIF2α Modulates Extra‐Hepatic Disease‐Associated Phenotypes During Metabolic Dysfunction‐Associated Steatotic Liver Disease

ABSTRACT Metabolic dysfunction‐associated steatotic liver disease (MASLD) afflicts more than one‐third of adults globally, contributing significantly to an increased cardiovascular disease risk. Further, patients with severe liver disease experience muscle weakness and fatigue. Hypoxia‐inducible factor 2α (HIF2α) accumulates in the livers of MASLD patients. Here we sought to understand the role of hepatic HIF2α in mediating hepatic and extra‐hepatic features of MASLD. Using an obese mouse model of MASLD, we investigated the impact of hepatocyte‐specific HIF2α deletion (hHIF2α −/− ) on hepatic, cardiac and skeletal muscle metabolism, and cardiac function. Over 28 weeks, mice were exposed to a high‐fat, high‐fructose, high‐cholesterol (GAN) diet, which induced obesity, hepatic steatosis, fibrosis and inflammation. hHIF2α −/− was associated with greater hepatic NADH‐supported mitochondrial respiration, higher sphingomyelin levels and protection against MASLD induced hyperinsulinaemia, but not against hepatic manifestations of MASLD. Instead, in the hearts of GAN‐fed mice, hHIF2α −/− caused diacylglycerol and long‐chain acyl‐carnitine accumulation and exacerbated diet‐induced ceramide accumulation. Langendorff‐perfused hearts from hHIF2α −/− mice showed systolic and diastolic dysfunction, including 24% lower left ventricular developed pressure and 34% lower maximal rate of relaxation (dP/dt min ). However, isolated hearts from hHIF2α −/− mice were protected against MASLD‐associated sympathetic dominance, determined using autonomic receptor agonist stimulation. Both GAN‐feeding and hHIF2α −/− were associated with lower lean mass (14% and 5.4% lower than respective controls), whilst hHIF2α −/− enhanced OXPHOS‐associated protein levels in gastrocnemius muscle. Overall, hHIF2α −/− resulted in detrimental extra‐hepatic effects, including myocardial lipid accumulation, impaired cardiac function, and loss of whole‐body lean mass, thereby worsening the systemic presentation of MASLD‐associated pathological features.