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Proceedings of the National Academy of Sciences of the United States of America logoLink to Proceedings of the National Academy of Sciences of the United States of America
. 1982 Oct;79(20):6355–6359. doi: 10.1073/pnas.79.20.6355

Difference in saturable binding of low density lipoprotein to liver membranes from normocholesterolemic subjects and patients with heterozygous familial hypercholesterolemia.

K Harders-Spengel, C B Wood, G R Thompson, N B Myant, A K Soutar
PMCID: PMC347120  PMID: 6292899

Abstract

To investigate the possible role of the low density lipoprotein (LDL) receptor in the catabolism of LDL by the human liver, the binding of 125I-labeled LDL to membrane fractions prepared from human liver biopsies was determined. Biopsy samples taken for routine histology were obtained from seven patients with heterozygous familial hypercholesterolemia, one with non-familial hypercholesterolemia, and seven normocholesterolemic subjects. LDL was bound by the membranes from normal subjects in a saturable manner that was inhibited by 56% in the presence of excess LDL. Binding of LDL was also inhibited by modification of the lipoproteins with 1,2-cyclohexanedione. The amount of 125I-labeled LDL bound to membranes from familial hypercholesterolemic livers that could be displaced with excess LDL was significantly less than that bound by normocholesterolemic membranes. These observations suggest that LDL receptors are expressed in normal human liver and are defective in the livers of familial hypercholesterolemic patients.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Basu S. K., Goldstein J. L., Brown M. S. Characterization of the low density lipoprotein receptor in membranes prepared from human fibroblasts. J Biol Chem. 1978 Jun 10;253(11):3852–3856. [PubMed] [Google Scholar]
  2. Brown M. S., Goldstein J. L. Familial hypercholesterolemia: defective binding of lipoproteins to cultured fibroblasts associated with impaired regulation of 3-hydroxy-3-methylglutaryl coenzyme A reductase activity. Proc Natl Acad Sci U S A. 1974 Mar;71(3):788–792. doi: 10.1073/pnas.71.3.788. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Brown M. S., Kovanen P. T., Goldstein J. L. Receptor-mediated uptake of lipoprotein-cholesterol and its utilization for steroid synthesis in the adrenal cortex. Recent Prog Horm Res. 1979;35:215–257. doi: 10.1016/b978-0-12-571135-7.50009-6. [DOI] [PubMed] [Google Scholar]
  4. HAVEL R. J., EDER H. A., BRAGDON J. H. The distribution and chemical composition of ultracentrifugally separated lipoproteins in human serum. J Clin Invest. 1955 Sep;34(9):1345–1353. doi: 10.1172/JCI103182. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Hui D. Y., Innerarity T. L., Mahley R. W. Lipoprotein binding to canine hepatic membranes. Metabolically distinct apo-E and apo-B,E receptors. J Biol Chem. 1981 Jun 10;256(11):5646–5655. [PubMed] [Google Scholar]
  6. Kita T., Brown M. S., Watanabe Y., Goldstein J. L. Deficiency of low density lipoprotein receptors in liver and adrenal gland of the WHHL rabbit, an animal model of familial hypercholesterolemia. Proc Natl Acad Sci U S A. 1981 Apr;78(4):2268–2272. doi: 10.1073/pnas.78.4.2268. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Knight B. L., Soutar A. K. Degradation by cultured fibroblasts and macrophages of unmodified and 1,2-cyclohexanedione-modified low-density lipoprotein from normal and homozygous familial hypercholesterolaemic subjects. Biochem J. 1982 Jan 15;202(1):145–152. doi: 10.1042/bj2020145. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Kovanen P. T., Basu S. K., Goldstein J. L., Brown M. S. Low density lipoprotein receptors in bovine adrenal cortex. II. Low density lipoprotein binding to membranes prepared from fresh tissue. Endocrinology. 1979 Mar;104(3):610–616. doi: 10.1210/endo-104-3-610. [DOI] [PubMed] [Google Scholar]
  9. Kovanen P. T., Brown M. S., Basu S. K., Bilheimer D. W., Goldstein J. L. Saturation and suppression of hepatic lipoprotein receptors: a mechanism for the hypercholesterolemia of cholesterol-fed rabbits. Proc Natl Acad Sci U S A. 1981 Mar;78(3):1396–1400. doi: 10.1073/pnas.78.3.1396. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Kovanen P. T., Brown M. S., Goldstein J. L. Increased binding of low density lipoprotein to liver membranes from rats treated with 17 alpha-ethinyl estradiol. J Biol Chem. 1979 Nov 25;254(22):11367–11373. [PubMed] [Google Scholar]
  11. LOWRY O. H., ROSEBROUGH N. J., FARR A. L., RANDALL R. J. Protein measurement with the Folin phenol reagent. J Biol Chem. 1951 Nov;193(1):265–275. [PubMed] [Google Scholar]
  12. Mahley R. W., Hui D. Y., Innerarity T. L., Weisgraber K. H. Two independent lipoprotein receptors on hepatic membranes of dog, swine, and man. Apo-B,E and apo-E receptors. J Clin Invest. 1981 Nov;68(5):1197–1206. doi: 10.1172/JCI110365. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Mahley R. W., Innerarity T. L., Pitas R. E., Weisgraber K. H., Brown J. H., Gross E. Inhibition of lipoprotein binding to cell surface receptors of fibroblasts following selective modification of arginyl residues in arginine-rich and B apoproteins. J Biol Chem. 1977 Oct 25;252(20):7279–7287. [PubMed] [Google Scholar]
  14. McFARLANE A. S. Efficient trace-labelling of proteins with iodine. Nature. 1958 Jul 5;182(4627):53–53. doi: 10.1038/182053a0. [DOI] [PubMed] [Google Scholar]
  15. Myant N. B. Cholesterol transport through the plasma. Clin Sci (Lond) 1982 Mar;62(3):261–271. doi: 10.1042/cs0620261. [DOI] [PubMed] [Google Scholar]
  16. Shepherd J., Bicker S., Lorimer A. R., Packard C. J. Receptor-mediated low density lipoprotein catabolism in man. J Lipid Res. 1979 Nov;20(8):999–1006. [PubMed] [Google Scholar]
  17. Spengel F. A., Jadhav A., Duffield R. G., Wood C. B., Thompson G. R. Superiority of partial ileal bypass over cholestyramine reducing cholesterol in familial hypercholesterolaemia. Lancet. 1981 Oct 10;2(8250):768–770. doi: 10.1016/s0140-6736(81)90183-5. [DOI] [PubMed] [Google Scholar]

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