Over the course of evolution, aerobic organisms have developed sophisticated systems for responding to alterations in oxygen concentration, as oxygen acts as a final electron acceptor in oxidative phosphorylation for energy production. Hypoxia-inducible factor (HIF) plays a central role in the adaptive regulation of energy metabolism, by triggering a switch from mitochondrial oxidative phosphorylation to anaerobic glycolysis in hypoxic conditions. HIF also reduces oxygen consumption in mitochondria by inhibiting conversion of pyruvate to acetyl CoA, suppressing mitochondrial biogenesis and activating autophagy of mitochondria concomitantly with reduction in reactive oxygen species production. In addition, metabolic reprogramming in response to hypoxia through HIF activation is not limited to the regulation of carbohydrate metabolism; it occurs in lipid metabolism as well. Recent studies using in vivo gene-targeting technique have revealed unexpected, but novel functions of HIF in energy metabolism in a context-and cell type-specific manner, and shed light on the possibility of pharmaceutical targeting HIF as a new therapy against many diseases, including cancer, diabetes, and fatty liver.

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The liver is a central organ that metabolizes excessive nutrients for storage in the form of glycogen and lipids and supplies energy-producing substrates to the peripheral tissues to maintain their function, even under starved conditions. These processes require a considerable amount of oxygen, which causes a steep oxygen gradient throughout the hepatic lobules. Alcohol consumption and/or excessive food intake can alter the hepatic metabolic balance drastically, which can precipitate fatty liver disease, a major cause of chronic liver diseases worldwide, ranging from simple steatosis, through steatohepatitis and hepatic fibrosis, to liver cirrhosis. Altered hepatic metabolism and tissue remodeling in fatty liver disease further disrupt hepatic oxygen homeostasis, resulting in severe liver hypoxia. As master regulators of adaptive responses to hypoxic stress, hypoxia-inducible factors (HIFs) modulate various cellular and organ functions, including erythropoiesis, angiogenesis, metabolic demand, and cell survival, by activating their target genes during fetal development and also in many disease conditions such as cancer, heart failure, and diabetes. In the past decade, it has become clear that HIFs serve as key factors in the regulation of lipid metabolism and fatty liver formation. This review discusses the molecular mechanisms by which hypoxia and HIFs regulate lipid metabolism in the development and progression of fatty liver disease.