Saturation and suppression of hepatic lipoprotein receptors: A mechanism for the hypercholesterolemia of cholesterol-fed rabbits (fi very low density lipoprotein/low density lipoprotein/apoproteins B and E/regulation of receptors/clearance of plasma lipoproteins)

Cholesterol-fed rabbits develop a marked in- crease in plasma cholesterol levels. Most of the excess plasma cho- lesterol is contained in a-migrating very low density lipoprotein (P-VLDL), a cholesterol-rich particle that contains apoproteins B and E. When 1251-labeled fi-VLDL from cholesterol-fed rabbits was injected intravenously into normal rabbits, the lipoprotein was cleared rapidly from plasma, 80% of the radioactivity ap- pearing in the liver within 4 min. in vitro binding assays showed that this uptake was due to the presence on liver membranes of a high-affinity, low-capacity binding site that resembles the low density lipoprotein receptor previously characterized on extra- hepatic tissues. When the '251-labeled P-VLDL was injected into cholesterol-fed rabbits, hepatic uptake was reduced by more than 95% and the lipoprotein remained in the plasma. This defective uptake in cholesterol-fed rabbits was due to two factors: (i) satu- ration of the lipoprotein receptors by the high concentration of endogenous plasma fl-VLDL and (ii) a 60% reduction in the num- ber of hepatic receptors after cholesterol feeding. Of the two fac- tors, saturation of receptors was quantitatively more important. We suggest that, as a result of the saturation and suppression of receptors, the hepatic removal of fi-VLDL in the cholesterol-fed rabbit fails to increase commensurate with the diet-induced in- crease in /3-VLDL synthesis and profound hypercholesterolemia ensues. The rabbit is unique among animal species in its extreme sen- sitivity to dietary cholesterol. Within days after the initiation of a high cholesterol diet, the plasma cholesterol level rises more than 10-fold. Most of the excess plasma cholesterol is con-