The cellular responses to low oxygen levels (hypoxia), as occurs at high altitude, are critical for survival. The transcription factor, hypoxia inducible factor 1 (HIF-1), is a key player in this setting, upregulating genes that preserve function. Included in these are glycolysis enzymes, which allow ATP synthesis in an O2-independent manner, and vascular endothelial growth factor (VEGF), which promotes angiogenesis. HIFs are also important in development and deletion of HIF-1 in mammals is perinatally lethal.
HIF-1 occurs as a heterodimer of HIF-1α and the constitutively expressed HIF-1β. Under normal oxygen conditions, HIF-1α is a substrate for HIF-1 prolyl hydroxylases and the asparagine hydroxylase, factor inhibiting HIF-1α (FIH). The action of the prolyl hydroxylases results in the targeting of HIF-1α by an E3 ubiquitin ligase and subsequent degradation by the proteasome, whilst hydroxylation by FIH represses activity of its carboxy terminal transactivation domain (CAD). Both hydroxylation processes therefore serve to down-regulate the activity of HIF-1. When oxygen levels are low, however, the prolyl hydroxylases and FIH become inactive since they are dependent on O2.
A team led by researchers at University of California at San Diego have now reported on a FIH-knockout mouse. Despite the importance of HIF-1 in development, the FIH-deleted mice were healthy, although smaller than wild-type littermates. Where they differed significantly was in their metabolic profile. The FIH-null mice exhibited elevated metabolic rate, enhanced insulin sensitivity, hyperventilation and improved lipid and glucose homeostasis. On a high-fat diet, the animals were resistant to weight gain and had reduced central adiposity.
The team went on to explore the effects of tissue-specific FIH deletion, demonstrating that most of the features of the metabolic phenotype of the FIH-null mice could be replicated when only neuronal FIH was deleted.
The study, published in Cell Metabolism, identifies FIH as an essential regulator of metabolism and opens up the possibility of FIH inhibitors for the treatment of metabolic disorders.