Influence of Fatty Acids on Cholesterol Synthesis of Hepatocytes in Monolayer Culture

The short-term (6-hour) and long-term (72-hour) influences of a wide spectrum of fatty acids on cholesterogenesis in monolayer cultures of rat hepatocytes were studied. A 6-hour addition of 0.5 mmol/liter of oleate to the culture medium raised 3-hydroxy-3-methylglutaryl-CoA reductase [mevalonate:NADP+ oxidoreductase (CoA-acylating), EC 1.1.1.34] activity by 62%. Octanoate, palmitate, stearate, linoleate, arachidonate and linolenate did not change enzyme activity significantly under these circumstances. A 72-hour incubation led to a 162% rise of enzyme activity by oleate and a 33% lowering by arachidonate, the other long-chain fatty acids having no significant effect (linoleate, linolenate, palmitate and stearate). These modulations of enzyme activity were paralleled by comparable changes of cholesterogenesis as measured by incorporation of [1-14C]acetate into cholesterol. The results are compatible with the concept that the response of hepatic cholesterogenesis to dietary triglycerides in vivo (observed by earlier investigators) is due to influences of the triglyceride fatty acids on hepatocyte 3-hydroxy-3-methylglutaryl-CoA reductase activity.