A B S T R A C T The effect of clofibrate (CPIB) on hepatic glycerolipid formation has been studied in vivo and in vitro in the rat. Feeding 0.25% CPIB in laboratory chow significantly reduced serum triglyceride levels by 6 hr and concomitantly decreased the rate of glycerol-4C incorporation into hepatic and serum glycerides, in vivo. These changes persisted for at least 14 days. A similar decrease in serum triglyceride and glycerol incorporation into hepatic glycerides was observed in rats fed high glucose diets containing 0.25% CPIB. Serum glycerol was reduced by feeding CPIB for 14 days. The formation of diglyceride and triglyceride from 14C-snglycerol-3-P by rat liver homogenates was inhibited by addition of 1-40 mm CPIB to the reaction mixture. These results suggest that CPIB reduces hepatic glycerolipid synthesis, possibly by inhibition of one or more reactions in the esterification of sn-glycerol-3-P. This change may account for the early fall in serum triglyceride. At later time periods, serum glycerol levels fall and in some experiments, hepatic triglyceride content increases. Therefore, it is likely that additional metabolic alterations may contribute to the sustained hypotriglyceridemic effects of CPIB.

Clofibrate and betabenzalbutyrate produce a variety of metabolic alterations in vivo. These include reduction in serum triglyceride and alterations in adipose tissue uptake and release of lipids. Clofibrate displaces thyroxine from albumin binding sites and produces an enlargement of liver and changes in ultrastructure. The biochemical changes produced by clofibrate include reduction in adenyl cyclase activity, inhibition of acetyl CoA carboxylase, inhibition of cholesterol biosynthesis and inhibition of triglyceride formation. Recent studies in this laboratory have shown that the inhibition of hepatic triglyceride formation is an early metabolic consequence of clofibrate administration and precedes the fall in serum triglyceride and several of the other biochemical alterations. Moreover clofibrate and betabenzalbutyrate inhibit the esterification ofsn‐glycerol‐3‐P by rat liver homogenate and microsomal preparations. The initial step in this pathway, acyl‐CoA‐sn‐glycerol‐3‐P acyltransferase, is inhibited by both drugs, in vitro. It is possible that this in vitro inhibition explains the early hypotriglyceridemic effect of these agents.

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