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. 1986 Nov;78(5):1206–1219. doi: 10.1172/JCI112704

Familial apolipoprotein E deficiency.

E J Schaefer, R E Gregg, G Ghiselli, T M Forte, J M Ordovas, L A Zech, H B Brewer Jr
PMCID: PMC423806  PMID: 3771793

Abstract

A unique kindred with premature cardiovascular disease, tubo-eruptive xanthomas, and type III hyperlipoproteinemia (HLP) associated with familial apolipoprotein (apo) E deficiency was examined. Homozygotes (n = 4) had marked increases in cholesterol-rich very low density lipoproteins (VLDL) and intermediate density lipoproteins (IDL), which could be effectively lowered with diet and medication (niacin, clofibrate). Homozygotes had only trace amounts of plasma apoE, and accumulations of apoB-48 and apoA-IV in VLDL, IDL, and low density lipoproteins. Radioiodinated VLDL apoB and apoE kinetic studies revealed that the homozygous proband had markedly retarded fractional catabolism of VLDL apoB-100, apoB-48 and plasma apoE, as well as an extremely low apoE synthesis rate as compared to normals. Obligate heterozygotes (n = 10) generally had normal plasma lipids and mean plasma apoE concentrations that were 42% of normal. The data indicate that homozygous familial apoE deficiency is a cause of type III HLP, is associated with markedly decreased apoE production, and that apoE is essential for the normal catabolism of triglyceride-rich lipoprotein constituents.

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Selected References

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

  1. Anderson D. W., Nichols A. V., Pan S. S., Lindgren F. T. High density lipoprotein distribution. Resolution and determination of three major components in a normal population sample. Atherosclerosis. 1978 Feb;29(2):161–179. doi: 10.1016/0021-9150(78)90005-9. [DOI] [PubMed] [Google Scholar]
  2. Basu S. K., Ho Y. K., Brown M. S., Bilheimer D. W., Anderson R. G., Goldstein J. L. Biochemical and genetic studies of the apoprotein E secreted by mouse macrophages and human monocytes. J Biol Chem. 1982 Aug 25;257(16):9788–9795. [PubMed] [Google Scholar]
  3. Blanche P. J., Gong E. L., Forte T. M., Nichols A. V. Characterization of human high-density lipoproteins by gradient gel electrophoresis. Biochim Biophys Acta. 1981 Sep 24;665(3):408–419. doi: 10.1016/0005-2760(81)90253-8. [DOI] [PubMed] [Google Scholar]
  4. Blum C. B., Aron L., Sciacca R. Radioimmunoassay studies of human apolipoprotein E. J Clin Invest. 1980 Dec;66(6):1240–1250. doi: 10.1172/JCI109975. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Boyles J. K., Pitas R. E., Wilson E., Mahley R. W., Taylor J. M. Apolipoprotein E associated with astrocytic glia of the central nervous system and with nonmyelinating glia of the peripheral nervous system. J Clin Invest. 1985 Oct;76(4):1501–1513. doi: 10.1172/JCI112130. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Brewer H. B., Jr, Zech L. A., Gregg R. E., Schwartz D., Schaefer E. J. NIH conference. Type III hyperlipoproteinemia: diagnosis, molecular defects, pathology, and treatment. Ann Intern Med. 1983 May;98(5 Pt 1):623–640. doi: 10.7326/0003-4819-98-5-623. [DOI] [PubMed] [Google Scholar]
  7. Dietary and drug treatment of primary hyperlipoproteinemia. Ann Intern Med. 1972 Aug;77(2):267–294. doi: 10.7326/0003-4819-77-2-267. [DOI] [PubMed] [Google Scholar]
  8. Ehrenberg L., Moustacchi E., Osterman-Golkar S. International Commission for Protection Against Environmental Mutagens and Carcinogens. Dosimetry of genotoxic agents and dose-response relationships of their effects. Mutat Res. 1983 Oct;123(2):121–182. doi: 10.1016/0165-1110(83)90024-6. [DOI] [PubMed] [Google Scholar]
  9. Fredrickson D. S., Levy R. I., Lees R. S. Fat transport in lipoproteins--an integrated approach to mechanisms and disorders. N Engl J Med. 1967 Jan 26;276(4):215–contd. doi: 10.1056/NEJM196701262760406. [DOI] [PubMed] [Google Scholar]
  10. Ghiselli G., Schaefer E. J., Gascon P., Breser H. B., Jr Type III hyperlipoproteinemia associated with apolipoprotein E deficiency. Science. 1981 Dec 11;214(4526):1239–1241. doi: 10.1126/science.6795720. [DOI] [PubMed] [Google Scholar]
  11. Ghiselli G., Schaefer E. J., Zech L. A., Gregg R. E., Brewer H. B., Jr Increased prevalence of apolipoprotein E4 in type V hyperlipoproteinemia. J Clin Invest. 1982 Aug;70(2):474–477. doi: 10.1172/JCI110638. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Glomset J. A., Applegate K., Forte T., King W. C., Mitchell C. D., Norum K. R., Gjone E. Abnormalities in lipoproteins of d < 1.006 g/ml in familial lecithin:cholesterol acyltransferase deficiency. J Lipid Res. 1980 Nov;21(8):1116–1127. [PubMed] [Google Scholar]
  13. Gregg R. E., Ghiselli G., Brewer H. B., Jr Apolipoprotein EBethesda: a new variant of apolipoprotein E associated with type III hyperlipoproteinemia. J Clin Endocrinol Metab. 1983 Nov;57(5):969–974. doi: 10.1210/jcem-57-5-969. [DOI] [PubMed] [Google Scholar]
  14. Gregg R. E., Zech L. A., Schaefer E. J., Brewer H. B., Jr Apolipoprotein E metabolism in normolipoproteinemic human subjects. J Lipid Res. 1984 Nov;25(11):1167–1176. [PubMed] [Google Scholar]
  15. Gregg R. E., Zech L. A., Schaefer E. J., Brewer H. B., Jr Type III hyperlipoproteinemia: defective metabolism of an abnormal apolipoprotein E. Science. 1981 Feb 6;211(4482):584–586. doi: 10.1126/science.7455696. [DOI] [PubMed] [Google Scholar]
  16. Havel R. J., Kotite L., Kane J. P., Tun P., Bersot T. Atypical familial dysbetalipoproteinemia associated with apolipoprotein phenotype E3/3. J Clin Invest. 1983 Jul;72(1):379–387. doi: 10.1172/JCI110978. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Hoeg J. M., Demosky S. J., Jr, Gregg R. E., Schaefer E. J., Brewer H. B., Jr Distinct hepatic receptors for low density lipoprotein and apolipoprotein E in humans. Science. 1985 Feb 15;227(4688):759–761. doi: 10.1126/science.2982214. [DOI] [PubMed] [Google Scholar]
  18. Krauss R. M., Burke D. J. Identification of multiple subclasses of plasma low density lipoproteins in normal humans. J Lipid Res. 1982 Jan;23(1):97–104. [PubMed] [Google Scholar]
  19. Kushwaha R. S., Hazzard W. R., Gagne C., Chait A., Albers J. J. Type III hyperlipoproteinemia: paradoxical hypolipidemic response to estrogen. Ann Intern Med. 1977 Nov;87(5):517–525. doi: 10.7326/0003-4819-87-5-517. [DOI] [PubMed] [Google Scholar]
  20. 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]
  21. Meng M. S., Gregg R. E., Schaefer E. J., Hoeg J. M., Brewer H. B., Jr Presence of two forms of apolipoprotein B in patients with dyslipoproteinemia. J Lipid Res. 1983 Jul;24(7):803–809. [PubMed] [Google Scholar]
  22. Nestel P. J., Billington T., Fidge N. H. Slower removal of intestinal apolipoprotein B-48 than of apolipoprotein B-100 in severely hypertriglyceridemic subjects. Biochim Biophys Acta. 1983 May 16;751(3):422–427. doi: 10.1016/0005-2760(83)90301-6. [DOI] [PubMed] [Google Scholar]
  23. Norum R. A., Lakier J. B., Goldstein S., Angel A., Goldberg R. B., Block W. D., Noffze D. K., Dolphin P. J., Edelglass J., Bogorad D. D. Familial deficiency of apolipoproteins A-I and C-III and precocious coronary-artery disease. N Engl J Med. 1982 Jun 24;306(25):1513–1519. doi: 10.1056/NEJM198206243062503. [DOI] [PubMed] [Google Scholar]
  24. Papadopoulos N. M. Abrnomal lipoprotein patterns in human serum as determined by agarose gel electrophoresis. Clin Chem. 1979 Nov;25(11):1885–1887. [PubMed] [Google Scholar]
  25. Rall S. C., Jr, Weisgraber K. H., Innerarity T. L., Bersot T. P., Mahley R. W., Blum C. B. Identification of a new structural variant of human apolipoprotein E, E2(Lys146 leads to Gln), in a type III hyperlipoproteinemic subject with the E3/2 phenotype. J Clin Invest. 1983 Oct;72(4):1288–1297. doi: 10.1172/JCI111085. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Rall S. C., Jr, Weisgraber K. H., Innerarity T. L., Mahley R. W. Structural basis for receptor binding heterogeneity of apolipoprotein E from type III hyperlipoproteinemic subjects. Proc Natl Acad Sci U S A. 1982 Aug;79(15):4696–4700. doi: 10.1073/pnas.79.15.4696. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Rall S. C., Jr, Weisgraber K. H., Mahley R. W. Human apolipoprotein E. The complete amino acid sequence. J Biol Chem. 1982 Apr 25;257(8):4171–4178. [PubMed] [Google Scholar]
  28. Schaefer E. J. Clinical, biochemical, and genetic features in familial disorders of high density lipoprotein deficiency. Arteriosclerosis. 1984 Jul-Aug;4(4):303–322. doi: 10.1161/01.atv.4.4.303. [DOI] [PubMed] [Google Scholar]
  29. Schaefer E. J., Foster D. M., Zech L. A., Lindgren F. T., Brewer H. B., Jr, Levy R. I. The effects of estrogen administration on plasma lipoprotein metabolism in premenopausal females. J Clin Endocrinol Metab. 1983 Aug;57(2):262–267. doi: 10.1210/jcem-57-2-262. [DOI] [PubMed] [Google Scholar]
  30. Schaefer E. J., Heaton W. H., Wetzel M. G., Brewer H. B., Jr Plasma apolipoprotein A-1 absence associated with a marked reduction of high density lipoproteins and premature coronary artery disease. Arteriosclerosis. 1982 Jan-Feb;2(1):16–26. doi: 10.1161/01.atv.2.1.16. [DOI] [PubMed] [Google Scholar]
  31. Schaefer E. J., Jenkins L. L., Brewer H. B., Jr Human chylomicron apolipoprotein metabolism. Biochem Biophys Res Commun. 1978 Jan 30;80(2):405–412. doi: 10.1016/0006-291x(78)90691-5. [DOI] [PubMed] [Google Scholar]
  32. Schaefer E. J., Levy R. I., Anderson D. W., Danner R. N., Brewer H. B., Jr, Blackwelder W. C. Plasma-triglycerides in regulation of H.D.L.-cholesterol levels. Lancet. 1978 Aug 19;2(8086):391–393. doi: 10.1016/s0140-6736(78)91863-9. [DOI] [PubMed] [Google Scholar]
  33. Schaefer E. J., Levy R. I. Pathogenesis and management of lipoprotein disorders. N Engl J Med. 1985 May 16;312(20):1300–1310. doi: 10.1056/NEJM198505163122007. [DOI] [PubMed] [Google Scholar]
  34. Schaefer E. J., Ordovas J. M., Law S. W., Ghiselli G., Kashyap M. L., Srivastava L. S., Heaton W. H., Albers J. J., Connor W. E., Lindgren F. T. Familial apolipoprotein A-I and C-III deficiency, variant II. J Lipid Res. 1985 Sep;26(9):1089–1101. [PubMed] [Google Scholar]
  35. Schaefer E. J., Zech L. A., Jenkins L. L., Bronzert T. J., Rubalcaba E. A., Lindgren F. T., Aamodt R. L., Brewer H. B., Jr Human apolipoprotein A-I and A-II metabolism. J Lipid Res. 1982 Aug;23(6):850–862. [PubMed] [Google Scholar]
  36. Sparks C. E., Rader D. J., Marsh J. B. Metabolism of two forms of apolipoprotein B of VLDL by rat liver. J Lipid Res. 1983 Feb;24(2):156–166. [PubMed] [Google Scholar]
  37. Stalenhoef A. F., Malloy M. J., Kane J. P., Havel R. J. Metabolism of apolipoproteins B-48 and B-100 of triglyceride-rich lipoproteins in normal and lipoprotein lipase-deficient humans. Proc Natl Acad Sci U S A. 1984 Mar;81(6):1839–1843. doi: 10.1073/pnas.81.6.1839. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Tyroler H. A., Heiss G., Schonfeld G., Cooper G., Heyden S., Hames C. G. Apolipoprotein A-I, A-II and C-II in black and white residents of Evans County. Circulation. 1980 Aug;62(2):249–254. doi: 10.1161/01.cir.62.2.249. [DOI] [PubMed] [Google Scholar]
  39. Utermann G., Jaeschke M., Menzel J. Familial hyperlipoproteinemia type III: deficiency of a specific apolipoprotein (apo E-III) in the very-low-density lipoproteins. FEBS Lett. 1975 Aug 15;56(2):352–355. doi: 10.1016/0014-5793(75)81125-2. [DOI] [PubMed] [Google Scholar]
  40. Utermann G., Kindermann I., Kaffarnik H., Steinmetz A. Apolipoprotein E phenotypes and hyperlipidemia. Hum Genet. 1984;65(3):232–236. doi: 10.1007/BF00286508. [DOI] [PubMed] [Google Scholar]
  41. Van't Hooft F. M., Hardman D. A., Kane J. P., Havel R. J. Apolipoprotein B (B-48) of rat chylomicrons is not a precursor of the apolipoprotein of low density lipoproteins. Proc Natl Acad Sci U S A. 1982 Jan;79(1):179–182. doi: 10.1073/pnas.79.1.179. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Warnick G. R., Benderson J., Albers J. J. Dextran sulfate-Mg2+ precipitation procedure for quantitation of high-density-lipoprotein cholesterol. Clin Chem. 1982 Jun;28(6):1379–1388. [PubMed] [Google Scholar]
  43. Wilson P. W., Zech L. A., Gregg R. E., Schaefer E. J., Hoeg J. M., Sprecher D. L., Brewer H. B., Jr Estimation of VLDL cholesterol in hyperlipidemia. Clin Chim Acta. 1985 Oct 15;151(3):285–291. doi: 10.1016/0009-8981(85)90091-9. [DOI] [PubMed] [Google Scholar]
  44. Zannis V. I., Breslow J. L. Human very low density lipoprotein apolipoprotein E isoprotein polymorphism is explained by genetic variation and posttranslational modification. Biochemistry. 1981 Feb 17;20(4):1033–1041. doi: 10.1021/bi00507a059. [DOI] [PubMed] [Google Scholar]
  45. Zannis V. I., Ordovas J. M., Cladaras C., Cole F. S., Forbes G., Schaefer E. J. mRNA and apolipoprotein E synthesis abnormalities in peripheral blood monocyte macrophages in familial apolipoprotein E deficiency. J Biol Chem. 1985 Oct 25;260(24):12891–12894. [PubMed] [Google Scholar]

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