Hypoxia-inducible factors and their roles in energy metabolism

Abstract

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.

Progress on hypoxia-inducible factor-3: Its structure, gene regulation and biological function (Review)

“…They positively regulate the expression levels of >100 target genes, which encode protein products involved in the response to hypoxia (3)(4)(5). Tumor hypoxia was first described in the 1950s and currently there is increasing evidence to demonstrate that hypoxia is regulated by HIFs and is a common feature in several types of cancer (6)(7)(8)(9).…”

FOXM1 regulates glycolysis in hepatocellular carcinoma by transactivating glucose transporter 1 expression

“…A previous study showed that oncogenes and tumor-suppressor genes participate in cancer metabolism via the dysregulation of key metabolism-related molecules, including glycolysis-related transporters (GLUTs and MCTs) and glycolytic enzymes (G6PI and HK2). For example, HIF, either alone or together with the oncogene MYC, was shown to promote glycolysis by activating glucose transporters, glycolytic enzymes and lactate dehydrogenase A (LDHA) (5,(19)(20)(21). Therefore, we detected the expression changes of all glycolysis-related molecules in HepG2 and MHCC-97H cell lines when FOXM1 was knocked down.…”

Depletion of suppressor of cytokine signaling-1a causes hepatic steatosis and insulin resistance in zebrafish

“…As a result of enhanced lipolysis and gluconeogenesis activities in the socs1a-deficient liver, these activities should consume a large amount of oxygen to produce energy (14). It is conceivable that lipid metabolism is related to hypoxia sensing, particularly in aquatic vertebrates.…”

“…5A). Hif-mediated metabolic approaches appear to be important for the maintenance of local oxygen homeostasis in the liver by either limiting oxygen consumption or promoting fatty acid oxidation to glycolysis and blocking mitochondrial biogenesis (14). Because of the highly activated GH signaling in socs1a mutant fish, glycolysis activity is inhibited.…”