Hepatic low density lipoprotein receptors, HMG-CoA reductase, and plasma lipids and apolipoproteins in high- and low-responding rhesus monkeys: Effect of cholestyramine treatment

Plasma lipids and apolipoproteins, and hepatic LDL receptor and HMG-CoA reductase activities in biopsy samples were measured in high- and low-responding rhesus monkeys maintained on a cholesterol-rich and regular diets. The effect of a 30-day cholestyramine treatment on the above parameters under both dietary conditions was also determined. On the cholesterol-rich diet the high-responders, when compared to the low-responders, had several-fold increased plasma cholesterol and apoB concentrations and significantly lower HDL apoA-I and cholesterol concentrations. Hepatic LDL receptor and HMG-CoA reductase activities were not detectable in the high-responders, while the low-responders expressed a reduced number of LDL receptors of normal affinity. Administration of cholestyramine resulted in a rapid induction of the hepatic LDL receptors in the high-responders and a small additional increase in the low-responders. Cholestyramine treatment also stimulated the expression of the hepatic HMG-CoA reductase in both groups of monkeys. These changes were accompanied by a dramatic drop in plasma cholesterol and apoB concentrations in the high-responders and, to a lesser extent, in the low-responders. Plasma HDL concentrations in the high-responders rose to levels higher than those seen in the low-responders. The affinity and receptor number were similar in both groups of monkeys on the control diet, but the low-responders had significantly higher HMG-CoA reductase activities. Administration of cholestyramine during the control diet had a small but significant additional effect on the hepatic LDL receptors of the low-responders but not of the high-responders. An additional increase in the hepatic HMG-CoA reductase activity of both groups of animals was also observed. It is concluded that the observed differences in the rate of intestinal absorption of dietary cholesterol (Bhattacharyya, A.K., and D.A. Eggen. 1981. J. Lipid Res. 21: 518-524) appear to be thus far the only difference in the manner the two groups of monkeys handle cholesterol. The increased dietary input in the high-responders results in complete down-regulation of the hepatic LDL receptor and, as a consequence, accumulation of apoB and associated cholesterol in plasma. The lower input of dietary cholesterol in the low-responders allows for the expression of a measurable amount of hepatic LDL receptors to maintain nearly normal plasma concentrations of apoB and associated cholesterol.