Short-term inhibition of fatty acid biosynthesis in isolated hepatocytes by mono-aromatic compounds

Abstract

An overview is presented of a selected number of mono-aromatic derivatives and their short-term effects on hepatic fatty acid biosynthesis. The compounds discussed in this paper are ortho-hydroxybenzoate (salicylate), meta-hydroxybenzoate, para-hydroxybenzoate, benzoate, para-t-butylbenzoate, para-aminosalicylate, clofibrate, halofenate, alpha-cyano-4-hydroxycinnamate and benfluorex. All of these drugs inhibit fatty acid biosynthesis by isolated rat liver cells, albeit with different effectiveness. In contrast, the compounds have differential effects on fatty acid esterification and oxidation by isolated hepatocytes. An attempt is made to describe in molecular terms the underlying mechanisms of the acute inhibitory effects of the mono-aromatic derivatives on hepatic lipogenesis. It is proposed that all of the drugs exert an inhibitory action at the level of acetyl-CoA carboxylase, the enzyme generally considered to catalyse the rate-limiting step in hepatic fatty acid synthesis. This inhibitory effect may be either direct, i.e. by an alteration of the enzyme's structure as a result of interaction between drug and enzyme, or indirect, i.e. through a drug-induced change in the cellular levels of allosteric effectors of acetyl-CoA carboxylase.