Comparison of the effects of clofibrate and halofenate (MK-185) in isolated rat hepatocytes

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      Both clofibrate and halofenate reduce serum lipids in hyperlipidemic subjects. Although several studies have reported alterations in hepatic lipid metabolism after clofibrate-feeding to animals, little work has been done to determine the effects of these drugs in vitro. In the present study with isolated rat hepatocytes, CPIB significantly inhibited acetate, incorporation into cellular lipids. Since oxidation of acetate to CO2 was not inhibited by similar concentrations of CPIB, it is concluded that the reduction in lipid synthesis did not result from inhibition of acetate thiokinase. Isolation of labeled products by thin-layer chromatography revealed an equal reduction of acetate incorporation into all lipid classes. Halofenate was approximately thirty times more potent than clofibrate in decreasing lipid synthesis from [14C]acetate. Whereas CPIB had no affect on [14C]leucine incorporation into protein, halofenate also inhibited this pathway. Each drug increased both the esterification and oxidation of [14C]-palmitate, suggesting that displacement of fatty acids from albumin was responsible. Although halofenate was a more potent inhibitor of lipid synthesis than clofibrate, the latter drug was more specific in its action.

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