dc.contributor.author | Pearce, N. J. | |
dc.contributor.author | Yates, J. W. | |
dc.contributor.author | Berkhout, Theo | |
dc.contributor.author | Jackson, B. | |
dc.contributor.author | Tew, D. | |
dc.contributor.author | Boyd, H. | |
dc.contributor.author | Camilleri, P. | |
dc.contributor.author | Sweeney, P. | |
dc.contributor.author | Gribble, Andrew D. | |
dc.contributor.author | Shaw, A. | |
dc.contributor.author | Groot, P. H. E. | |
dc.date.accessioned | 2014-06-11T11:30:37Z | |
dc.date.available | 2014-06-11T11:30:37Z | |
dc.date.issued | 1998-08-15 | |
dc.identifier.citation | Pearce , N J , Yates , J W , Berkhout , T , Jackson , B , Tew , D , Boyd , H , Camilleri , P , Sweeney , P , Gribble , A D , Shaw , A & Groot , P H E 1998 , ' 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 ' , Biochemical Journal , vol. 334 , no. 1 , pp. 113-119 . | |
dc.identifier.issn | 0264-6021 | |
dc.identifier.uri | http://hdl.handle.net/2299/13703 | |
dc.description.abstract | 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 γ-lactone prodrug of the potent ATP citrate-lyase inhibitor SB-201076 (K(i) = 1 μM). 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. | en |
dc.format.extent | 7 | |
dc.language.iso | eng | |
dc.relation.ispartof | Biochemical Journal | |
dc.subject | Biochemistry | |
dc.title | 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 | en |
dc.contributor.institution | School of Life and Medical Sciences | |
dc.contributor.institution | Department of Pharmacy | |
dc.contributor.institution | Health & Human Sciences Research Institute | |
dc.contributor.institution | Medicinal and Analytical Chemistry | |
dc.description.status | Peer reviewed | |
rioxxterms.type | Journal Article/Review | |
herts.preservation.rarelyaccessed | true | |