DIFFERENCES IN PROPIONATE-INDUCED INHIBITION OF CHOLESTEROL AND TRIACYLGLYCEROL SYNTHESIS BETWEEN HUMAN AND RAT HEPATOCYTES IN PRIMARY CULTURE

Propionate is a short-chain fatty acid formed in the colon and suppose dly involved in the cholesterol-lowering effect of soluble fibre. To e xplore the underlying mechanism(s) of this fibre action, we have used human hepatocytes in primary culture to study the effects of propionat e on hepatic lipid synthesis. Initial experiments with mevalonate and mevinolin, a competitive inhibitor of hydroxymethylglutaryl (HMG)-Coa reductase (EC 1.1.1.88) were performed to evaluate basic regulatory me chanisms in these cells; results were compared with those obtained wit h rat hepatocytes. Incubation for 24 h with mevalonate caused a simila r, concentration-dependent inhibition of [C-14]acetate incorporation i nto cholesterol in human and rat hepatocytes. Likewise, mevinolin (100 mu mol/l) inhibited the formation of cholesterol from radiolabelled a cetate by about 80% in cells from both species. Propionate inhibited c holesterol as well as triacylglycerol synthesis from [C-14]acetate wit h a similar concentration-dependency in rat hepatocytes. Fifty percent inhibition was obtained at a propionate concentration of only 0.1 mmo l/l. This propionate-induced inhibition was not affected by a 100-fold excess of unlabelled acetate. Human hepatocytes were much less suscep tible in this respect: propionate concentrations of 10-20 mmol/l were required to obtain similar inhibitory effects in these cells, i.e. val ues greatly exceeding reported portal propionate concentrations in hum ans. The results suggest the existence of differences in the regulatio n of hepatic cholesterol (and triacylglycerol) synthesis between human and rat Liver cells. These results do not support the hypothesis that the fibre-induced decrease in plasma cholesterol concentration in man is mediated by a direct effect of propionate on hepatic cholesterol s ynthesis.