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.

摘要: 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 potential target hypolipidaemic intervention. Here we describe the biological effects of inhibition citrate-lyase on lipid metabolism in Hep G2 cells, plasma lipids rats dogs, by using SB-204990, cell-penetrant gamma-lactone prodrug potent inhibitor SB-201076 (Ki=1 microM). Consistent with an important role supply units SB-204990 inhibited cells (dose-related up to 91% 82% respectively) (76% 39% respectively). when administered orally rats, was absorbed into systemic circulation; pharmacologically relevant concentrations were recovered liver. When diet (0.05-0. 25%, w/w) 1 week, caused dose-related decrease (by 46%) triglyceride levels 80%) rats. This effect could be explained, at least part, (up 48%) hepatic very-low-density lipoprotein (VLDL) production as measured accumulation VLDL after injection Triton WR-1339. (25 mg/kg per day) also decreased 23%) 38%) dog, preferentially decreasing low-density compared high-density levels. Overall these results are consistent concept controlling substrate novo