Saturation and suppression of hepatic lipoprotein receptors: a mechanism for the hypercholesterolemia of cholesterol-fed rabbits.

Abstract

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.

• Authors: P T Kovanen, M S Brown, S K Basu, D W Bilheimer, J L Goldstein
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 78 Issue 3 Pg. 1396-400 (Mar 1981) ISSN: 0027-8424 [Print] United States
• PMID: 6262794 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Cholesterol, Dietary
• Lipoproteins, HDL
• Lipoproteins, VLDL
• Receptors, Cell Surface
• Receptors, Lipoprotein

Topics

• Adrenal Glands (metabolism)
• Animals
• Cell Membrane (metabolism)
• Cholesterol, Dietary (pharmacology)
• Humans
• Hypercholesterolemia (metabolism)
• Kinetics
• Lipoproteins, HDL (metabolism)
• Lipoproteins, VLDL (metabolism)
• Liver (metabolism)
• Male
• Rabbits
• Receptors, Cell Surface (drug effects, metabolism)
• Receptors, Lipoprotein