Histone deacetylase HDAC8 and insulin resistance

Insulin resistance is a pathological condition contributed by both genetic and environmental factors. In normal individuals, insulin functions to signal the liver, muscles, and adipose tissues to maintain blood glucose within physiological levels. When insulin resistance occurs, glucose accumulates in blood and contributes to the development of type 2 diabetes. At molecular level, the changes of metabolites in blood and different organs can be detected by cells, wherein proteins like histone deacetylases (HDACs) can respond by epigenetically modifying the gene expression in related metabolic pathways. The functions of HDACs are diverse, which are facilitated by their mobility among cellular compartments for targeting both nuclear and cytoplasmic protein substrates. Overexpression of HDACs is mostly pathogenic, which can disrupt insulin turnover and glucose homeostasis through different mechanisms in multiple organs. In the case of HDAC8, systemic obesity causes the activation of sterol regulatory element-binding protein-1 (SREBP-1) that binds to and upregulates HDAC8. Such augmented HDAC8 drives the expression of WNT signaling components and cooperates with enhancer of zeste homolog 2 (EZH2) to transcriptionally silence WNT antagonist genes. These effects and other molecular signaling changes promote glucose accumulation, insulin resistance, and development of other fatty liver-associated diseases and hepatocellular carcinoma. Given the consistent pathogenic effects of HDACs in different diseases, a large collection of HDAC inhibitors have been developed as novel therapeutic drugs, and some of which have demonstrated promising clinical effects in certain diseases despite side effects and durability concerns. These issues are expected to be addressed with the continual improvements of HDAC inhibitors. In particular, optimization of HDAC8 inhibitors holds great therapeutic potential owing to the unique targetable structure in HDAC8 compared with other HDAC isoforms.