Hypoxia-Inducible Factor 2 Regulates Hepatic Lipid Metabolism

Abstract

In mammals, the liver integrates nutrient uptake and delivery of carbohydrates and lipids to peripheral tissues to control overall energy balance. Hepatocytes maintain metabolic homeostasis by coordinating gene expression programs in response to dietary and systemic signals. Hepatic tissue oxygenation is an important systemic signal that contributes to normal hepatocyte function as well as disease. Hypoxia-inducible factors 1 and 2 (HIF-1 and HIF-2, respectively) are oxygen-sensitive heterodimeric transcription factors, which act as key mediators of cellular adaptation to low oxygen. Previously, we have shown that HIF-2 plays an important role in both physiologic and pathophysiologic processes in the liver. HIF-2 is essential for normal fetal EPO production and erythropoiesis, while constitutive HIF-2 activity in the adult results in polycythemia and vascular tumorigenesis. Here we report a novel role for HIF-2 in regulating hepatic lipid metabolism. We found that constitutive activation of HIF-2 in the adult results in the development of severe hepatic steatosis associated with impaired fatty acid ␤-oxidation, decreased lipogenic gene expression, and increased lipid storage capacity. These findings demonstrate that HIF-2 functions as an important regulator of hepatic lipid metabolism and identify HIF-2 as a potential target for the treatment of fatty liver disease.The liver plays a central role in maintaining overall organism energy balance by controlling carbohydrate and lipid metabolism. Hepatocytes coordinate these processes by regulating gene expression programs in response to dietary signals from the portal vein and systemic signals from the hepatic artery. Oxygen is an important systemic signal that modulates metabolic activities and disease in the liver. Under physiologic conditions, an oxygen gradient is established in the liver such that the partial pressure of oxygen in periportal blood is 60 to 65 mm Hg and in the perivenous blood is 30 to 35 mm Hg (17). This oxygen gradient is important for the zonation of metabolic activity in the liver. Because oxygen is an essential electron acceptor for oxidative metabolism, hepatocytes that perform glucose or fatty acid oxidation are located in the aerobic periportal zone, whereas oxygen-independent metabolic functions such as glucose uptake, glycolysis, and fatty acid synthesis are predominately performed by perivenous hepatocytes (16). Patients who experience perivenous hypoxia as a result of heart failure, obstructive sleep apnea, or excessive alcohol use can develop chronic liver injury characterized by steatosis and inflammation (17). Therefore, it is critical that oxygen-signaling pathways in hepatocytes are appropriately integrated into adaptive and/or maladaptive liver injury responses.Hypoxia-inducible transcription factors (HIFs) are important components of the cellular oxygen-signaling pathway. In response to low oxygen tensions, HIFs facilitate both oxygen delivery and adaptation to oxygen deprivation by regulating the expression of genes that are i...

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