Coenzyme A: diacylglycerol acyltransferase 1 inhibitor ameliorates obesity, liver steatosis, and lipid metabolism abnormality in KKAy mice fed high-fat or high-carbohydrate diets.
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.
Yamamoto
Toshihiro
T
Pharmacology Research Laboratories, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Osaka, Japan. Yamamoto_Toshihiro@takeda.co.jp
Yamaguchi
Hiroshi
H
Miki
Hiroshi
H
Shimada
Mitsuyuki
M
Nakada
Yoshihisa
Y
Ogino
Masaki
M
Asano
Kouhei
K
Aoki
Kazuko
K
Tamura
Norikazu
N
Masago
Minori
M
Kato
Koki
K
D000042:Absorption / Q000187:drug effects; D050154:Adiposity / Q000187:drug effects; D000818:Animals; D002784:Cholesterol / Q000097:blood / Q000378:metabolism; D051048:Diacylglycerol O-Acyltransferase / Q000037:antagonists & inhibitors*; D004040:Dietary Carbohydrates / Q000009:adverse effects*; D004041:Dietary Fats / Q000009:adverse effects*; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D005234:Fatty Liver / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism; D005260:Female; D050356:Lipid Metabolism / Q000187:drug effects*; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D009765:Obesity / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism; D013997:Time Factors; D014280:Triglycerides / Q000378:metabolism
D004040:Dietary Carbohydrates; D004041:Dietary Fats; D004791:Enzyme Inhibitors; D014280:Triglycerides; D002784:Cholesterol; D051048:Diacylglycerol O-Acyltransferase