Destabilization of HIF-1a by Diabetes, Oxidative Stress, Obesity and Other Related Disorders

Abstract

One of the most fundamental molecular processes in response to hypoxia is the activation and stabilization of a transcriptional factor called hypoxia induced factor 1a (HIF-1a), which is responsible for the regulation of many downstream effector genes. Multiple key biological pathways such as proliferation, energy metabolism, invasion, and metastasis are governed by these genes. This article discusses the role of hypoxia-inducible factor 1a (HIF-1a) in metabolic and pathological processes, particularly in adipose tissue, oxidative stress, inflammation, diabetes and cancer. HIF1A is a basic helix-loophelix PAS domain containing protein, and is considered as the master transcriptional regulator of cellular and developmental response to hypoxia. HIF-1a regulates the expression of genes involved in angiogenesis, glucose metabolism, inflammation and oxidative stress. In obesity, adipose tissue hypoxia leads to increased expression of HIF-1a, which can lead to chronic inflammation and adipose tissue dysfunction. Another field that HIF-1a is also involved in cancer pathogenesis pathways, such as proliferation, invasion, angiogenesis, and metastasis, and is considered a potential therapeutic target for metabolic/genetic diseases and cancer. Direct and indirect HIF-1 inhibitors have been identified, but only a few have entered clinical trials due to their multiple side effects.