The role of hypoxia-inducible factors in metabolic diseases

• Published in: Nature reviews. Endocrinology Vol. 15; no. 1; pp. 21 - 32
• Main Authors: Gonzalez, Frank J, Xie, Cen, Jiang, Changtao
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 01.01.2019
• Subjects: Adipocytes; Adiponectin; Adipose tissue; Angiogenesis; Animals; Cancer; Cell proliferation; Cellular signal transduction; Clinical trials; Development and progression; Diabetes mellitus; Diabetes mellitus (non-insulin dependent); Diabetes Mellitus, Type 2 - genetics; Diabetes Mellitus, Type 2 - physiopathology; Diet; Fatty liver; Female; Gene Expression Regulation; Health aspects; Humans; Hypoxia; Hypoxia-Inducible Factor 1 - genetics; Hypoxia-inducible factor 1a; Inflammation; Insulin; Insulin resistance; Kidney cancer; Liver diseases; Male; Medical research; Medicine, Experimental; Metabolic diseases; Metabolic Diseases - genetics; Metabolic Diseases - physiopathology; Metabolic disorders; Metabolic regulation; Mice; Mice, Knockout; Non-alcoholic Fatty Liver Disease - genetics; Non-alcoholic Fatty Liver Disease - physiopathology; Obesity; Obesity - genetics; Obesity - physiopathology; Phenotypes; Physiological aspects; Proteolysis; Sensitivity and Specificity; Serum levels; Signal transduction; Signal Transduction - genetics; Small intestine; SOCS-3 protein; Stat3 protein; Transcription factors; Transcription, Genetic; United States
• ISSN: 1759-5029; 1759-5037
• DOI: 10.1038/s41574-018-0096-z

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.