Therapeutic Strategies for Metabolic Diseases: Small-Molecule Diacylglycerol Acyltransferase (DGAT) Inhibitors

Metabolic diseases such as atherogenic dyslipidemia, hepatic steatosis, obesity, and type II diabetes are emerging as major global health problems. Acyl-CoA:diacylglycerol acyltransferase (DGAT) is responsible for catalyzing the final reaction in the glycerol phosphate pathway of triglycerol synthesis. It has two isoforms, DGAT-1 and DGAT-2, which are widely expressed and present in white adipose tissue. DGAT-1 is most highly expressed in the small intestine, whereas DGAT-2 is primarily expressed in the liver. Therefore, the selective inhibition of DGAT-1 has become an attractive target with growing potential for the treatment of obesity and type II diabetes. Furthermore, DGAT-2 has been suggested as a new target for the treatment of DGAT-2-related liver diseases including hepatic steatosis, hepatic injury, and fibrosis. In view the discovery of drugs that target DGAT, herein we attempt to provide insight into the scope and further reasons for optimization of DGAT inhibitors. Pathway barricades: Herein we summarize all potent diacylglycerol acyltransferase (DGAT) inhibitors derived from various natural sources (i.e., plants and microorganisms) and from synthetic chemical libraries. This review emphasizes the functions of DGATs along with their importance as therapeutic targets for the treatment of metabolic disorders.