Improving Insulin Sensitivity With HDAC Inhibitor

  1. Jianping Ye
  1. Antioxidant and Gene Regulation Laboratory, Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge, Louisiana
  1. Corresponding author: Jianping Ye, yej{at}pbrc.edu.

Histone deacetylase (HDAC) has emerged as a new molecular target in the control of obesity and type 2 diabetes. HDAC is an enzyme with well-known functions in the regulation of chromatin structure and gene transcription in the nucleus, where HDAC interacts with corepressor proteins such as NcoR and SMRT to form active corepressor complexes. In the corepressor complex, HDAC catalyzes removal of acetyl groups from histone proteins to inhibit gene expression. Recent studies have consistently suggested that HDAC also exhibits activity in the cytosol and mitochondria to regulate acetylation of metabolic enzymes (1). More than 20% of mitochondria proteins are regulated by acetylation (2,3). Regulation of HDAC activity is a new approach to modify glucose and fatty acid metabolism in the treatment of type 2 diabetes.

In HDAC, HDAC3 and sirtuin (SIRT)1 are well-known players in regulation of fatty acid and glucose metabolism. In mammals, HDACs are divided into three classes: class I HDACs (13,8,10), class II HDACs (47,9,11), and class III HDACs (SIRTs 1–7 and NAD-dependent histone deacetylases). Class I HDACs have strong catalytic activities, and they are targets of most HDAC inhibitors, such as trichostatin A (TSA), sodium butyrate, and suberoylanilide hydroxamic acid. HDAC3 regulates metabolism in genetic and pharmacological studies. NcoR is required by HDAC3 in the regulation of transcription factors including peroxisome proliferator–activated receptor (PPAR)γ. NcoR knockout in fat tissue led to enhanced PPARγ function in adipose tissue, increased insulin sensitivity, …

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