Hepatic HIF2α Modulates Extra-Hepatic Disease-Associated Phenotypes During Metabolic Dysfunction-Associated Steatotic...

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.