Saturation and suppression of hepatic lipoprotein receptors: a mechanism for the hypercholesterolemia of cholesterol-fed rabbits.
Cholesterol-fed rabbits develop a marked in crease in plasma cholesterol levels. Most of the excess plasma cholesterol is contained in beta-migrating very low density lipoprotein (beta-VLDL), a cholesterol-rich particle that contains apoproteins B and E. When 125I-labeled beta-VLDL from cholesterol-fed rabbits was injected intravenously into normal rabbits, the lipoprotein was cleared rapidly from plasma, 80% of the radioactivity appearing 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 extrahepatic tissues. When the 125I-labeled beta-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) saturation of the lipoprotein receptors by the high concentration of endogenous plasma beta-VLDL and (ii) a 60% reduction in the number of hepatic receptors after cholesterol feeding. Of the two factors, saturation of receptors was quantitatively more important. We suggest that, as a result of the saturation and suppression of receptors, the hepatic removal of beta-VLDL in the cholesterol-fed rabbit fails to increase commensurate with the diet-induced increase in beta-VLDL synthesis and profound hypercholesterolemia ensues.
D000311:Adrenal Glands / Q000378:metabolism; D000818:Animals; D002462:Cell Membrane / Q000378:metabolism; D002791:Cholesterol, Dietary / Q000494:pharmacology*; D006801:Humans; D006937:Hypercholesterolemia / Q000378:metabolism*; D007700:Kinetics; D008075:Lipoproteins, HDL / Q000378:metabolism; D008079:Lipoproteins, VLDL / Q000378:metabolism; D008099:Liver / Q000378:metabolism*; D008297:Male; D011817:Rabbits; D011956:Receptors, Cell Surface / Q000187:drug effects / Q000378:metabolism*; D018110:Receptors, Lipoprotein
D002791:Cholesterol, Dietary; D008075:Lipoproteins, HDL; D008079:Lipoproteins, VLDL; D011956:Receptors, Cell Surface; D018110:Receptors, Lipoprotein