The role of hypoxia-inducible factors in metabolic diseases

Abstract

Hypoxia-inducible factors (HIFs), a family of transcription factors activated by hypoxia, consist of three α-subunits (HIF1α, HIF2α and HIF3α) and one β-subunit (HIF1β), which serves as a heterodimerization partner of the HIFα subunits. HIFα subunits are stabilized from constitutive degradation by hypoxia largely through lowering the activity of the oxygen-dependent prolyl hydroxylases that hydroxylate HIFα, leading to their proteolysis. HIF1α and HIF2α are expressed in different tissues and regulate target genes involved in angiogenesis, cell proliferation and inflammation, and their expression is associated with different disease states. HIFs have been widely studied because of their involvement in cancer, and HIF2α-specific inhibitors are being investigated in clinical trials for the treatment of kidney cancer. Although cancer has been the major focus of research on HIF, evidence has emerged that this pathway has a major role in the control of metabolism and influences metabolic diseases such as obesity, type 2 diabetes mellitus and non-alcoholic fatty liver disease. Notably increased HIF1α and HIF2α signalling in adipose tissue and small intestine, respectively, promotes metabolic diseases in diet-induced disease models. Inhibition of HIF1α and HIF2α decreases the adverse diet-induced metabolic phenotypes, suggesting that they could be drug targets for the treatment of metabolic diseases.

Adipocyte and lipid metabolism in cancer drug resistance

“…The high adiposity-linked oxidative stress reduces availability of free oxygen molecules and contributes to radioresistance. As previously discussed, obese adipose tissue generally experiences tissue hypoxia (127,(186)(187)(188)(189), and recruitment of obese adipocytes in tumor tissues further facilitates tumor hypoxia (3,19,124), thereby leading to resistance to radiation therapy.…”

Adipose tissue as a key player in obstructive sleep apnoea

“…Low circulating adiponectin levels are also associated with obesity and predictors of late cardiovascular events. Induction of HIF-1α in adipocytes, as demonstrated during IH, is known to lead to downregulation of adiponectin expression [48]. In a relatively large group of 486 obese subjects, plasma adiponectin levels gradually decreased with the increasing severity of OSA [49].…”

Hypoxia-inducible lipid droplet-associated interacts with DGAT1 and promotes lipid storage in hepatocytes

“…A pathological condition associated with upregulation of Hilpda is infection with hepatitis C virus (19), which, interestingly, uses lipid droplets for replication (1,27). Also, as HILPDA is highly induced by hypoxia, HILPDA is an excellent candidate to mediate the stimulatory effect of hypoxia/HIF1α on hepatic triglyceride levels, as seen in cancer cells (16,44).…”