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. 1994 May 10;91(10):4431–4435. doi: 10.1073/pnas.91.10.4431

The two-receptor model of lipoprotein clearance: tests of the hypothesis in "knockout" mice lacking the low density lipoprotein receptor, apolipoprotein E, or both proteins.

S Ishibashi 1, J Herz 1, N Maeda 1, J L Goldstein 1, M S Brown 1
PMCID: PMC43799  PMID: 8183926

Abstract

Apolipoprotein E (apoE) is hypothesized to mediate lipoprotein clearance by binding to two receptors: (i) the low density lipoprotein receptor (LDLR) and (ii) a chylomicron remnant receptor. To test this hypothesis, we have compared plasma lipoproteins in mice that are homozygous for targeted disruptions of the genes for apoE [apoE(-/-)], the LDLR [LDLR(-/-)], and both molecules [poE(-/-); LDLR(-/-)]. On a normal chow diet, apoE(-/-) mice had higher mean plasma cholesterol levels than LDLR(-/-) mice (579 vs. 268 mg/dl). Cholesterol levels in the apoE(-/-); LDLR(-/-) mice were not significantly different from those in the apoE(-/-) mice. LDLR(-/-) mice had a relatively isolated elevation in plasma LDL, whereas apoE(-/-) mice had a marked increase in larger lipoproteins corresponding to very low density lipoproteins and chylomicron remnants. The lipoprotein pattern in apoE(-/-); LDLR(-/-) mice resembled that of apoE(-/-) mice. The LDLR(-/-) mice had a marked elevation in apoB-100 and a modest increase in apoB-48. In contrast, the apoE(-/-) mice had a marked elevation in apoB-48 but not in apoB-100. The LDLR(-/-); apoE(-/-) double homozygotes had marked elevations of both apolipoproteins. The observation that apoB-48 increases more dramatically with apoE deficiency than with LDLR deficiency supports the notion that apoE binds to a second receptor in addition to the LDLR. This conclusion is also supported by the observation that superimposition of a LDLR deficiency onto an apoE deficiency [apoE(-/-); LDLR(-/-) double homozygotes] does not increase hypercholesterolemia beyond the level observed with apoE deficiency alone.

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Selected References

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  1. Bisgaier C. L., Sachdev O. P., Megna L., Glickman R. M. Distribution of apolipoprotein A-IV in human plasma. J Lipid Res. 1985 Jan;26(1):11–25. [PubMed] [Google Scholar]
  2. Brown M. S., Goldstein J. L. Lipoprotein receptors in the liver. Control signals for plasma cholesterol traffic. J Clin Invest. 1983 Sep;72(3):743–747. doi: 10.1172/JCI111044. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Delamatre J. G., Roheim P. S. The response of apolipoprotein A-IV to cholesterol feeding in rats. Biochim Biophys Acta. 1983 Apr 13;751(2):210–217. doi: 10.1016/0005-2760(83)90175-3. [DOI] [PubMed] [Google Scholar]
  4. Havel R. J., Kita T., Kotite L., Kane J. P., Hamilton R. L., Goldstein J. L., Brown M. S. Concentration and composition of lipoproteins in blood plasma of the WHHL rabbit. An animal model of human familial hypercholesterolemia. Arteriosclerosis. 1982 Nov-Dec;2(6):467–474. doi: 10.1161/01.atv.2.6.467. [DOI] [PubMed] [Google Scholar]
  5. Higuchi K., Kitagawa K., Kogishi K., Takeda T. Developmental and age-related changes in apolipoprotein B mRNA editing in mice. J Lipid Res. 1992 Dec;33(12):1753–1764. [PubMed] [Google Scholar]
  6. Innerarity T. L., Mahley R. W., Weisgraber K. H., Bersot T. P., Krauss R. M., Vega G. L., Grundy S. M., Friedl W., Davignon J., McCarthy B. J. Familial defective apolipoprotein B-100: a mutation of apolipoprotein B that causes hypercholesterolemia. J Lipid Res. 1990 Aug;31(8):1337–1349. [PubMed] [Google Scholar]
  7. Ishibashi S., Brown M. S., Goldstein J. L., Gerard R. D., Hammer R. E., Herz J. Hypercholesterolemia in low density lipoprotein receptor knockout mice and its reversal by adenovirus-mediated gene delivery. J Clin Invest. 1993 Aug;92(2):883–893. doi: 10.1172/JCI116663. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Ji Z. S., Brecht W. J., Miranda R. D., Hussain M. M., Innerarity T. L., Mahley R. W. Role of heparan sulfate proteoglycans in the binding and uptake of apolipoprotein E-enriched remnant lipoproteins by cultured cells. J Biol Chem. 1993 May 15;268(14):10160–10167. [PubMed] [Google Scholar]
  9. Kita T., Brown M. S., Bilheimer D. W., Goldstein J. L. Delayed clearance of very low density and intermediate density lipoproteins with enhanced conversion to low density lipoprotein in WHHL rabbits. Proc Natl Acad Sci U S A. 1982 Sep;79(18):5693–5697. doi: 10.1073/pnas.79.18.5693. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Kowal R. C., Herz J., Goldstein J. L., Esser V., Brown M. S. Low density lipoprotein receptor-related protein mediates uptake of cholesteryl esters derived from apoprotein E-enriched lipoproteins. Proc Natl Acad Sci U S A. 1989 Aug;86(15):5810–5814. doi: 10.1073/pnas.86.15.5810. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Kowal R. C., Herz J., Weisgraber K. H., Mahley R. W., Brown M. S., Goldstein J. L. Opposing effects of apolipoproteins E and C on lipoprotein binding to low density lipoprotein receptor-related protein. J Biol Chem. 1990 Jun 25;265(18):10771–10779. [PubMed] [Google Scholar]
  12. Mahley R. W. Apolipoprotein E: cholesterol transport protein with expanding role in cell biology. Science. 1988 Apr 29;240(4852):622–630. doi: 10.1126/science.3283935. [DOI] [PubMed] [Google Scholar]
  13. Plump A. S., Smith J. D., Hayek T., Aalto-Setälä K., Walsh A., Verstuyft J. G., Rubin E. M., Breslow J. L. Severe hypercholesterolemia and atherosclerosis in apolipoprotein E-deficient mice created by homologous recombination in ES cells. Cell. 1992 Oct 16;71(2):343–353. doi: 10.1016/0092-8674(92)90362-g. [DOI] [PubMed] [Google Scholar]
  14. Rubinsztein D. C., Cohen J. C., Berger G. M., van der Westhuyzen D. R., Coetzee G. A., Gevers W. Chylomicron remnant clearance from the plasma is normal in familial hypercholesterolemic homozygotes with defined receptor defects. J Clin Invest. 1990 Oct;86(4):1306–1312. doi: 10.1172/JCI114839. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Steinmetz A., Utermann G. Activation of lecithin: cholesterol acyltransferase by human apolipoprotein A-IV. J Biol Chem. 1985 Feb 25;260(4):2258–2264. [PubMed] [Google Scholar]
  16. Weisgraber K. H., Mahley R. W., Kowal R. C., Herz J., Goldstein J. L., Brown M. S. Apolipoprotein C-I modulates the interaction of apolipoprotein E with beta-migrating very low density lipoproteins (beta-VLDL) and inhibits binding of beta-VLDL to low density lipoprotein receptor-related protein. J Biol Chem. 1990 Dec 25;265(36):22453–22459. [PubMed] [Google Scholar]
  17. Willnow T. E., Goldstein J. L., Orth K., Brown M. S., Herz J. Low density lipoprotein receptor-related protein and gp330 bind similar ligands, including plasminogen activator-inhibitor complexes and lactoferrin, an inhibitor of chylomicron remnant clearance. J Biol Chem. 1992 Dec 25;267(36):26172–26180. [PubMed] [Google Scholar]
  18. Yamada N., Shames D. M., Havel R. J. Effect of low density lipoprotein receptor deficiency on the metabolism of apolipoprotein B-100 in blood plasma. Kinetic studies in normal and Watanabe heritable hyperlipidemic rabbits. J Clin Invest. 1987 Aug;80(2):507–515. doi: 10.1172/JCI113099. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Yokode M., Hammer R. E., Ishibashi S., Brown M. S., Goldstein J. L. Diet-induced hypercholesterolemia in mice: prevention by overexpression of LDL receptors. Science. 1990 Nov 30;250(4985):1273–1275. doi: 10.1126/science.2244210. [DOI] [PubMed] [Google Scholar]
  20. Zhang S. H., Reddick R. L., Piedrahita J. A., Maeda N. Spontaneous hypercholesterolemia and arterial lesions in mice lacking apolipoprotein E. Science. 1992 Oct 16;258(5081):468–471. doi: 10.1126/science.1411543. [DOI] [PubMed] [Google Scholar]

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