Regulation of cholesterol biosynthesis and 3-hydroxy-3-methylglutaryl coenzyme A reductase activity by chylomicron remnants in isolated hepatocytes and perfused liver.

Newly synthesized and native chylomicrons from cholesterol-fed rats and native chylomicrons from three individuals with type V lipoproteinemia failed to inhibit the overall rate of cholesterol synthesis in isolated hepatocytes from meal-fed rats when incubated for 60 min at 37°C. In contrast, the corresponding chylomicron remnants prepared in vitro from the respective native chylomicron preparations by treatment with post-heparin plasma or bovine milk lipoprotein lipase inhibited hepatocyte cholesterol synthesis markedly (47-95%) under identical conditions. The concentration of rat chylomicron remnants to cause 50% inhibition of cholesterol synthesis was found to be 50 pg of protein or 147 pg of cholesterol/ml of incubation medium. Furthermore, the chylomicron remnants markedly inhibited the incorporation f labeled acetate but not that of mevalonate into hepatocyte cholesterol indicating thereby that the remnants must inhibit cholesterol biosynthesis at a step prior to the formation f mevalonate. Since the conversion of 3-hydroxy-3-methylglutaryl coenzyme A to mevalonate is the only step prior to mevalonate formation from acetylcoenzyme A that involves the incorporation of tritium from 3Hz0 via NADPH, it is obvious that the remnants inhibit at the 3-hydroxy-3-methylglutaryl-CoA reductase step. Progressive time dependent inhibition of 3-hydroxy-3methylglutaryl-CoA reductase activity by chylomicron remnants but not by native chylomicron was observed in the perfused liver system. Analysis of the apoprotein pattern of the native and remnant chylomicrons revealed that there was a profound loss of apo C proteins whereas the proportion of apolipoproteins E, AI, and A ~ v increased in chylomicron remnants as compared to their native chylomicrons. Studies on the uptake of chylomicron remnants by the hepatocytes indicated that the remnant particle was taken up intact without prior hydrolysis of the cholesterol ester moiety and the nonparenchymal cells had no significant influence upon the uptake of the remnants by parenchymal cells.