Effects of F-1394, an acyl-CoA:cholesterol acyltransferase (ACAT) inhibitor, on ACAT activity in HepG2 cells and on hepatic secretion of lipids in Triton WR-1339-induced hyperlipidemic rats: possible role of hepatic ACAT in very low density lipoprotein secretion.
We examined the inhibitory potency of F-1394 ((1S,2S)-2-[3-(2,2-dimethylpropyl)-3-nonylureido]cyclohexane -1-yl 3-[(4R)-N-(2,2,5,5-tetramethyl-1,3-dioxane-4-carbonyl)amino]propionate), an acyl-CoA:cholesterol acyltransferase (ACAT) inhibitor, on ACAT activity and its hypolipidemic effect. F-1394 inhibited whole-cell ACAT activity in HepG2 cells with an IC50 value of 42 nM. The potency of F-1394 was greater than that of the five other ACAT inhibitors tested (YM-17E, CI-976, 57-118, CL-277,082 and DL-melinamide). In rats made hyperlipidemic by Triton WR-1339, F-1394 caused a reduction in the hepatic secretion rate of cholesterol. These data suggest that inhibition of hepatic ACAT activity helps to reduce very low density lipoprotein secretion from the liver into the circulation.
Aragane
K
K
Pharmaceuticals Research Laboratories, Fujirebio, Inc., Hachioji, Tokyo, Japan.
Kusunoki
J
J
Kitamine
T
T
Yamaura
T
T
Ohnishi
H
H
D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology; D002460:Cell Line; D003510:Cyclohexanes / Q000494:pharmacology*; D004146:Dioxanes / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D006949:Hyperlipidemias / Q000139:chemically induced / Q000188:drug therapy* / Q000503:physiopathology*; D050356:Lipid Metabolism; D008079:Lipoproteins, VLDL / Q000097:blood / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000502:physiology; D011092:Polyethylene Glycols / Q000633:toxicity; D051381:Rats; D002785:Sterol O-Acyltransferase / Q000037:antagonists & inhibitors* / Q000378:metabolism
D000924:Anticholesteremic Agents; D003510:Cyclohexanes; D004146:Dioxanes; D004791:Enzyme Inhibitors; C094918:F 1394; D008079:Lipoproteins, VLDL; D011092:Polyethylene Glycols; D002785:Sterol O-Acyltransferase; C016811:tyloxapol