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Eur J Pharmacol. 2010 Aug 25;640(1-3):243-9. doi: 10.1016/j.ejphar.2010.04.050. Epub 2010 May 16.

Coenzyme A: diacylglycerol acyltransferase 1 inhibitor ameliorates obesity, liver steatosis, and lipid metabolism abnormality in KKAy mice fed high-fat or high-carbohydrate diets.

Author information

1
Pharmacology Research Laboratories, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Osaka, Japan. Yamamoto_Toshihiro@takeda.co.jp

Abstract

Coenzyme A (CoA):diacylglycerol acyltransferase 1 (DGAT1) is 1 of the 2 known DGAT enzymes that catalyze the final and only committed step in triacylglycerol synthesis; this enzyme is considered to be a potential therapeutic target in metabolic disorders such as obesity and its related lipid abnormalities. Compound-Z, a novel specific small-molecule DGAT1 inhibitor, significantly reduced adipose tissue weight and tended to hepatic lipid accumulation in genetically obese KKAy mice. These actions were shown to almost the same extent in both a high-fat feeding condition in which triacylglycerols are synthesized mainly via exogenous fatty acid and a low-fat, high-carbohydrate feeding condition in which triacylglycerols are synthesized mainly via de novo fatty acid synthesis. This inhibitor also significantly reduced plasma and/or hepatic cholesterol levels in KKAy mice in a high-fat feeding condition. This cholesterol-lowering effect was suggested to be due to mainly decreases in cholesterol absorption from the small intestine. These results suggest that Compound-Z is a promising and attractive agent not only for the treatment of obesity but also hepatic steatosis and circulating lipid abnormalities that are the leading causes of atherosclerosis.

PMID:
20478303
DOI:
10.1016/j.ejphar.2010.04.050
[Indexed for MEDLINE]

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