The role of ATP citrate-lyase in the metabolic regulation of plasma lipids. Hypolipidaemic effects of SB-204990, a lactone prodrug of the potent ATP citrate-lyase inhibitor SB-201076.
ATP citrate (pro-S)-lyase (EC 4.1.3.8), a cytosolic enzyme that generates acetyl-CoA for cholesterol and fatty acid synthesis de novo, is a potential target for hypolipidaemic intervention. Here we describe the biological effects of the inhibition of ATP citrate-lyase on lipid metabolism in Hep G2 cells, and plasma lipids in rats and dogs, by using SB-204990, the cell-penetrant gamma-lactone prodrug of the potent ATP citrate-lyase inhibitor SB-201076 (Ki=1 microM). Consistent with an important role of ATP citrate-lyase in the supply of acetyl-CoA units for lipid synthesis de novo, SB-204990 inhibited cholesterol synthesis and fatty acid synthesis in Hep G2 cells (dose-related inhibition of up to 91% and 82% respectively) and rats (76% and 39% respectively). SB-204990, when administered orally to rats, was absorbed into the systemic circulation; pharmacologically relevant concentrations of SB-201076 were recovered in the liver. When administered in the diet (0.05-0. 25%, w/w) for 1 week, SB-204990 caused a dose-related decrease in plasma cholesterol (by up to 46%) and triglyceride levels (by up to 80%) in rats. This hypolipidaemic effect could be explained, at least in part, by a decrease (up to 48%) in hepatic very-low-density lipoprotein (VLDL) production as measured by the accumulation of VLDL in plasma after injection of Triton WR-1339. SB-204990 (25 mg/kg per day) also decreased plasma cholesterol levels (by up to 23%) and triglyceride levels (by up to 38%) in the dog, preferentially decreasing low-density lipoprotein compared with high-density lipoprotein cholesterol levels. Overall these results are consistent with the concept that ATP citrate-lyase is an important enzyme in controlling substrate supply for lipid synthesis de novo and a potential enzyme target for hypolipidaemic intervention.
Department of Vascular Biology, SmithKline Beecham Pharmaceuticals Ltd., New Frontiers Science Park (North), Third Avenue, Harlow, Essex CM19 5AW, U.K. Nigel_Pearce-1@SB_PHARM_RD.Com
N J
NJ
Pearce
J W
JW
Yates
T A
TA
Berkhout
B
B
Jackson
D
D
Tew
H
H
Boyd
P
P
Camilleri
P
P
Sweeney
A D
AD
Gribble
A
A
Shaw
P H
PH
Groot
D001275:ATP Citrate (pro-S)-Lyase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000818:Animals; D001682:Biological Availability; D002722:Chlorobenzenes / Q000494:pharmacology*; D002784:Cholesterol / Q000096:biosynthesis / Q000097:blood; D004285:Dogs; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005230:Fatty Acids, Nonesterified / Q000378:metabolism; D006706:Homeostasis / Q000187:drug effects; D006801:Humans; D000960:Hypolipidemic Agents / Q000494:pharmacology*; D007783:Lactones / Q000493:pharmacokinetics / Q000494:pharmacology*; D008055:Lipids / Q000097:blood*; D008099:Liver / Q000201:enzymology*; D008297:Male; D011355:Prodrugs / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000378:metabolism; D014280:Triglycerides / Q000097:blood; D014407:Tumor Cells, Cultured
D002722:Chlorobenzenes; D004791:Enzyme Inhibitors; D005230:Fatty Acids, Nonesterified; D000960:Hypolipidemic Agents; D007783:Lactones; D008055:Lipids; D011355:Prodrugs; D011994:Recombinant Proteins; C114634:SB 201076; D014280:Triglycerides; C112852:SB 204990; D002784:Cholesterol; D001275:ATP Citrate (pro-S)-Lyase