Histone deacetylase inhibitors target diabetes via chromatin remodeling or as chemical chaperones?
Globally, obesity and diabetes (particularly type 2 diabetes) represents a major challenge to world health. Despite decades of intense research efforts, the genetic basis involved in diabetes pathogenesis & conditions associated with obesity are still poorly understood. Recent advances have led to exciting new developments implicating epigenetics as an important mechanism underpinning diabetes and obesity related disease. One epigenetic mechanism known as the "histone code" describes the idea that specific patterns of post-translational modifications to histones act like a molecular "code" recognised and used by non-histone proteins to regulate specific chromatin functions. One modification which has received significant attention is that of histone acetylation. The enzymes which regulate this modification are described as lysine acetyltransferases or KATs and histone deacetylases or HDACs. Due to their conserved catalytic domain HDACs have been actively targeted as a therapeutic target. Some of the known inhibitors of HDACs (HDACi) have also been shown to act as "chemical chaperones" to alleviate diabetic symptoms. In this review, we discuss the available evidence concerning the roles of HDACs in regulating chaperone function and how this may have implications in the management of diabetes.
Lawless
M W
MW
Centre for Liver Disease, School of Medicine and Medical Science, Mater Misericordiae University Hospital, University College Dublin, Dublin, Ireland.
O'Byrne
K J
KJ
Gray
S G
SG
D000123:Acetyltransferases / Q000378:metabolism; D042002:Chromatin Assembly and Disassembly; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000201:enzymology*; D016503:Drug Delivery Systems; D004721:Endoplasmic Reticulum / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D015971:Gene Expression Regulation, Enzymologic; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000378:metabolism*; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D018832:Molecular Chaperones / Q000494:pharmacology; D009765:Obesity / Q000150:complications / Q000201:enzymology; D010654:Phenylbutyrates / Q000494:pharmacology
D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D007004:Hypoglycemic Agents; D018832:Molecular Chaperones; D010654:Phenylbutyrates; C075773:4-phenylbutyric acid; D000123:Acetyltransferases; C103393:kinamycin acetyltransferase I; D006655:Histone Deacetylases