Skip to main content
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1990 May;85(5):1542–1547. doi: 10.1172/JCI114602

Overexpression of human low density lipoprotein receptors leads to accelerated catabolism of Lp(a) lipoprotein in transgenic mice.

S L Hofmann 1, D L Eaton 1, M S Brown 1, W J McConathy 1, J L Goldstein 1, R E Hammer 1
PMCID: PMC296603  PMID: 2139667

Abstract

Lp(a) lipoprotein purified from human plasma bound with high affinity to isolated bovine LDL receptors on nitrocellulose blots and in a solid-phase assay. Lp(a) also competed with 125I-LDL for binding to human LDL receptors in intact fibroblasts. Binding led to cellular uptake of Lp(a) with subsequent stimulation of cholesterol esterification. After intravenous injection, human Lp(a) was cleared slowly from the plasma of normal mice. The clearance was markedly accelerated in transgenic mice that expressed large amounts of LDL receptors. We conclude that the covalent attachment of apo(a) to apo B-100 in Lp(a) does not interfere markedly with the ability of apo B-100 to bind to the LDL receptor and that this receptor has the potential to play a major role in clearance of Lp(a) from the circulation of intact humans.

Full text

PDF
1542

Images in this article

Selected References

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

  1. Armstrong V. W., Walli A. K., Seidel D. Isolation, characterization, and uptake in human fibroblasts of an apo(a)-free lipoprotein obtained on reduction of lipoprotein(a). J Lipid Res. 1985 Nov;26(11):1314–1323. [PubMed] [Google Scholar]
  2. Beisiegel U., Schneider W. J., Brown M. S., Goldstein J. L. Immunoblot analysis of low density lipoprotein receptors in fibroblasts from subjects with familial hypercholesterolemia. J Biol Chem. 1982 Nov 10;257(21):13150–13156. [PubMed] [Google Scholar]
  3. Brown M. S., Goldstein J. L. Plasma lipoproteins: teaching old dogmas new tricks. Nature. 1987 Nov 12;330(6144):113–114. doi: 10.1038/330113a0. [DOI] [PubMed] [Google Scholar]
  4. Daniel T. O., Schneider W. J., Goldstein J. L., Brown M. S. Visualization of lipoprotein receptors by ligand blotting. J Biol Chem. 1983 Apr 10;258(7):4606–4611. [PubMed] [Google Scholar]
  5. Davis C. G., Elhammer A., Russell D. W., Schneider W. J., Kornfeld S., Brown M. S., Goldstein J. L. Deletion of clustered O-linked carbohydrates does not impair function of low density lipoprotein receptor in transfected fibroblasts. J Biol Chem. 1986 Feb 25;261(6):2828–2838. [PubMed] [Google Scholar]
  6. Floren C. H., Albers J. J., Bierman E. L. Uptake of Lp (a) lipoprotein by cultured fibroblasts. Biochem Biophys Res Commun. 1981 Sep 30;102(2):636–639. doi: 10.1016/s0006-291x(81)80179-9. [DOI] [PubMed] [Google Scholar]
  7. Goldstein J. L., Basu S. K., Brown M. S. Receptor-mediated endocytosis of low-density lipoprotein in cultured cells. Methods Enzymol. 1983;98:241–260. doi: 10.1016/0076-6879(83)98152-1. [DOI] [PubMed] [Google Scholar]
  8. Goldstein J. L., Dana S. E., Brown M. S. Esterification of low density lipoprotein cholesterol in human fibroblasts and its absence in homozygous familial hypercholesterolemia. Proc Natl Acad Sci U S A. 1974 Nov;71(11):4288–4292. doi: 10.1073/pnas.71.11.4288. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Havekes L., Vermeer B. J., Brugman T., Emeis J. Binding of LP(a) to the low density lipoprotein receptor of human fibroblasts. FEBS Lett. 1981 Sep 28;132(2):169–173. doi: 10.1016/0014-5793(81)81153-2. [DOI] [PubMed] [Google Scholar]
  10. Hofmann S. L., Russell D. W., Brown M. S., Goldstein J. L., Hammer R. E. Overexpression of low density lipoprotein (LDL) receptor eliminates LDL from plasma in transgenic mice. Science. 1988 Mar 11;239(4845):1277–1281. doi: 10.1126/science.3344433. [DOI] [PubMed] [Google Scholar]
  11. Innerarity T. L., Weisgraber K. H., Arnold K. S., Mahley R. W., Krauss R. M., Vega G. L., Grundy S. M. Familial defective apolipoprotein B-100: low density lipoproteins with abnormal receptor binding. Proc Natl Acad Sci U S A. 1987 Oct;84(19):6919–6923. doi: 10.1073/pnas.84.19.6919. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Krempler F., Kostner G. M., Roscher A., Haslauer F., Bolzano K., Sandhofer F. Studies on the role of specific cell surface receptors in the removal of lipoprotein (a) in man. J Clin Invest. 1983 May;71(5):1431–1441. doi: 10.1172/JCI110896. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Laemmli U. K. Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature. 1970 Aug 15;227(5259):680–685. doi: 10.1038/227680a0. [DOI] [PubMed] [Google Scholar]
  14. Maartmann-Moe K., Berg K. Lp(a) lipoprotein enters cultured fibroblasts independently of the plasma membrane low density lipoprotein receptor. Clin Genet. 1981 Nov;20(5):352–362. doi: 10.1111/j.1399-0004.1981.tb01047.x. [DOI] [PubMed] [Google Scholar]
  15. Schneider W. J., Goldstein J. L., Brown M. S. Purification of the LDL receptor. Methods Enzymol. 1985;109:405–417. doi: 10.1016/0076-6879(85)09106-6. [DOI] [PubMed] [Google Scholar]
  16. Soria L. F., Ludwig E. H., Clarke H. R., Vega G. L., Grundy S. M., McCarthy B. J. Association between a specific apolipoprotein B mutation and familial defective apolipoprotein B-100. Proc Natl Acad Sci U S A. 1989 Jan;86(2):587–591. doi: 10.1073/pnas.86.2.587. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Utermann G., Hoppichler F., Dieplinger H., Seed M., Thompson G., Boerwinkle E. Defects in the low density lipoprotein receptor gene affect lipoprotein (a) levels: multiplicative interaction of two gene loci associated with premature atherosclerosis. Proc Natl Acad Sci U S A. 1989 Jun;86(11):4171–4174. doi: 10.1073/pnas.86.11.4171. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Utermann G., Menzel H. J., Kraft H. G., Duba H. C., Kemmler H. G., Seitz C. Lp(a) glycoprotein phenotypes. Inheritance and relation to Lp(a)-lipoprotein concentrations in plasma. J Clin Invest. 1987 Aug;80(2):458–465. doi: 10.1172/JCI113093. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Utermann G. The mysteries of lipoprotein(a). Science. 1989 Nov 17;246(4932):904–910. doi: 10.1126/science.2530631. [DOI] [PubMed] [Google Scholar]
  20. Van Driel I. R., Brown M. S., Goldstein J. L. Stoichiometric binding of low density lipoprotein (LDL) and monoclonal antibodies to LDL receptors in a solid phase assay. J Biol Chem. 1989 Jun 5;264(16):9533–9538. [PubMed] [Google Scholar]
  21. Wong W. L., Eaton D. L., Berloui A., Fendly B., Hass P. E. A monoclonal-antibody-based enzyme-linked immunosorbent assay of lipoprotein(a). Clin Chem. 1990 Feb;36(2):192–197. [PubMed] [Google Scholar]
  22. Ye S. Q., Trieu V. N., Stiers D. L., McConathy W. J. Interactions of low density lipoprotein2 and other apolipoprotein B-containing lipoproteins with lipoprotein(a). J Biol Chem. 1988 May 5;263(13):6337–6343. [PubMed] [Google Scholar]

Articles from Journal of Clinical Investigation are provided here courtesy of American Society for Clinical Investigation

RESOURCES