Effects of free fatty acids on activity of hepatic microsomal 3-hydroxy-3-methylglutaryl coenzyme A reductase and on secretion of triglyceride and cholesterol by liver.

The output of triglyceride and cholesterol, and the activity of microsomal 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG-CoA reductase) were measured following perfusion of the isolated rat liver with a medium containing free fatty acids. The activity of the enzyme and the output of cholesterol and triglyceride are regulated by the quantity and structure of the free fatty acid. The activity of HMG-CoA reductase was linearly proportional to uptake of oleic acid (18:1) by the liver. Output of triglyceride and cholesterol in the presence of oleate was also stimulated although, under these experimental conditions, the maximal secretory rate for cholesterol was observed while reductase activity was still increasing. When equimolar quantities of palmitic (16:0), oleic (18:1), or linoleic acid (18:2) were infused, the observed activity of the enzyme was in the order 18:1 greater than 18:2 = 16:0. Output of triglyceride was in the order 18:1 = 18:2 greater than 16:0. Output of free and esterified cholesterol was in the order 18:1 greater than 18:2 greater than 16:0. The stimulation by free fatty acids of hepatic cholesterogenesis, as estimated by the activity of HMG-CoA reductase, probably is the result of stimulation by free fatty acids of secretion of triglyceride in the very low density lipoprotein, and the obligatory requirement for cholesterol as a component of the lipoprotein.