Pathogenesis of type III hyperlipoproteinemia (dysbetalipoproteinemia): Questions, quandaries, and paradoxes

Journal of Lipid Research

Volumn 40, Issue 11, 1999, Pages 1933-1949

  Mahley, Robert W ^a   Huang, Yadong ^a   Rall Jr , Stanley C ^a  

^a UNIVERSITY OF CALIFORNIA   (United States)

Author keywords

VLDL; Apolipoprotein E; Heparan sulfate proteoglycans; Hypercholesterolemia; Hypertriglyceridemia; LDL receptor; Lipolysis; Lipoprotein metabolism; Remnant lipoproteins; VLDL production

Indexed keywords

APOLIPOPROTEIN E; APOLIPOPROTEIN E2; ESTROGEN; LIPOPROTEIN; LOW DENSITY LIPOPROTEIN RECEPTOR; PROTEOHEPARAN SULFATE; VERY LOW DENSITY LIPOPROTEIN;

ATHEROSCLEROSIS; DISEASE ASSOCIATION; GENETIC SUSCEPTIBILITY; HOMOZYGOTE; HUMAN; HYPERCHOLESTEROLEMIA; HYPERLIPOPROTEINEMIA TYPE 3; HYPERTRIGLYCERIDEMIA; LIPOLYSIS; LIPOPROTEIN BLOOD LEVEL; NONHUMAN; PATHOGENESIS; PRIORITY JOURNAL; RECEPTOR BINDING; RECESSIVE INHERITANCE; REVIEW;

ANIMALS; APOLIPOPROTEIN E2; APOLIPOPROTEINS E; ARTERIOSCLEROSIS; FEMALE; HOMOZYGOTE; HUMANS; HYPERLIPOPROTEINEMIA TYPE III; LIPOPROTEINS; MALE;

EID: 0032743737     PISSN: 00222275     EISSN: None     Source Type: Journal    
DOI: None     Document Type: Review

References (127)

1. Mahley, R. W. 1988. Apolipoprotein E: cholesterol transport protein with expanding role in cell biology. Science. 240: 622-630.
2. Mahley, R. W., and S. C. Rall, Jr. 1995. Type III hyperlipoproteinemia (dysbetalipoproteinemia): the role of apolipoprotein E in normal and abnormal lipoprotein metabolism. In The Metabolic and Molecular Bases of Inherited Disease. 7th edition. C. R. Scriver, A. L. Beaudet, W. S. Sly, and D. Valle, editors. McGraw-Hill, New York. 1953-1980.
3. Mahley, R. W., and Z-S. Ji. 1999. Remnant lipoprotein metabolism: Key pathways involving cell-surface heparan sulfate proteoglycans and apolipoprotein E. J. Lipid Res. 40: 1-16.
4. Mahley, R. W., K. H. Weisgraber, and R. V. Farese, Jr. 1998. Disorders of lipid metabolism. In Williams Textbook of Endocrinology. 9th edition. J. D. Wilson, D. W. Foster, H. M. Kronenberg, and P. R. Larsen, editors. W.B. Saunders, Philadelphia. 1099-1153.
5. Mahley, R. W., and Y. Huang. 1999. Apolipoprotein E: from atherosclerosis to Alzheimer's disease and beyond. Curr. Opin. Lipidol. 10: 207-217.
6. Schaefer, E. J., R. E. Gregg, G. Ghiselli, T. M. Forte, J. M. Ordovas, L. A. Zech, and H. B. Brewer, Jr. 1986. Familial apolipoprotein E deficiency. J. Clin. Invest. 78: 1206-1219.
7. Mabuchi, H., H. Itoh, M. Takeda, K. Kajinami, T. Wakasugi, J. Koizumi, R. Takeda, and C. Asagami. 1989. A young type III hyperlipoproteinemic patient associated with apolipoprotein E deficiency. Metabolism. 38: 115-119.
8. Morganroth, J., R. I. Levy, and D. S. Fredrickson. 1975. The biochemical, clinical, and genetic features of type III hyperlipoproteinemia. Ann. Intern. Med. 82: 158-174.
9. Fredrickson, D. S., R. I. Levy, and R. S. Lees. 1967. Fat transport in lipoproteins - an integrated approach to mechanisms and disorders. N. Engl. J. Med. 276: 34-44, 94-103, 148-156, 215-225, 273-281.
10. Hazzard, W. R., T. F. O'Donnell, and Y. L. Lee. 1975. Broad-β disease (type III hyperlipoproteinemia) in a large kindred. Evidence for a monogenic mechanism. Ann. Intern. Med. 82: 141-149.
11. Fainaru, M., R. W. Mahley, R. L. Hamilton, and T. L. Innerarity. 1982. Structural and metabolic heterogeneity of β-very low density lipoproteins from cholesterol-fed dogs and from humans with type III hyperlipoproteinemia. J. Lipid Res. 23: 702-714.
12. Utermann, G., M. Hees, and A. Steinmetz. 1977. Polymorphism of apolipoprotein E and occurrence of dysbetalipoproteinaemia in man. Nature. 269: 604-607.
13. Utermann, G., U. Langenbeck, U. Beisiegel, and W. Weber. 1980. Genetics of the apolipoprotein E system in man. Am. J. Hum. Genet. 32: 339-347.
14. Zannis, V. I., P. W. Just, and J. L. Breslow. 1981. Human apolipoprotein E isoprotein subclasses are genetically determined. Am. J. Hum. Genet. 33: 11-24.
15. Zannis, V. I., J. L. Breslow, G. Utermann, R. W. Mahley, K. H. Weisgraber, R. J. Havel, J. L. Goldstein, M. S. Brown, G. Schonfeld, W. R. Hazzard, and C. Blum. 1982. Proposed nomenclature of apoE isoproteins, apoE genotypes, and phenotypes. J. Lipid Res. 23: 911-914.
16. Rall, S. C., Jr., K. H. Weisgraber, T. L. Innerarity, and R. W. Mahley. 1982. Structural basis for receptor binding heterogeneity of apolipoprotein E from type III hyperlipoproteinemic subjects. Proc. Natl. Acad. Sci. USA. 79: 4696-4700.
17. Utermann, G. 1985. Genetic polymorphism of apolipoprotein E - impact on plasma lipoprotein metabolism. In Diabetes, Obesity and Hyperlipidemias - III. G. Crepaldi, A. Tiengo, and G. Baggio, editors. Elsevier Science Publishers, Amsterdam. 1-28.
18. Davignon, J., R. E. Gregg, and C. F. Sing. 1988. Apolipoprotein E polymorphism and atherosclerosis. Arteriosclerosis. 8: 1-21.
19. Cooper, A. D. 1997. Hepatic uptake of chylomicron remnants. J. Lipid Res. 38: 2173-2192.
20. Brown, M. S., and J. L. Goldstein. 1986. A receptor-mediated pathway for cholesterol homeostasis. Science. 232: 34-47.
21. Brown, M. S., and J. L. Goldstein. 1983. Lipoprotein receptors in the liver. Control signals for plasma cholesterol traffic. J. Clin. Invest. 72: 743-747.
22. Herz, J., U. Hamann, S. Rogne, O. Myklebost, H. Gausepohl, and K. K. Stanley. 1988. Surface location and high affinity for calcium of a 500-kd liver membrane protein closely related to the LDL-receptor suggest a physiological role as lipoprotein receptor. EMBO J. 7: 4119-4127.
23. Herz, J., and T. E. Willnow. 1994. Functions of the LDL receptor gene family. Ann. NY Acad. Sci. 737: 14-19.
24. Brown, M. S., J. Herz, R. C. Kowal, and J. L. Goldstein. 1991. The low-density lipoprotein receptor-related protein: double agent or decoy? Curr. Opin. Lipidol. 2: 65-72.
25. Herz, J., and T. E. Willnow. 1995. Lipoprotein and receptor interactions in vivo. Curr. Opin. Lipidol. 6: 97-103.
26. Ji, Z-S., W. J. Brecht, R. D. Miranda, M. M. Hussain, T. L. Innerarity, and R. W. Mahley. 1993. Role of heparan sulfate proteoglycans in the binding and uptake of apolipoprotein E-enriched remnant lipoproteins by cultured cells. J. Biol. Chem. 268: 10160-10167.
27. Ji, Z-S., S. Fazio, Y-L. Lee, and R. W. Mahley. 1994. Secretion-capture role for apolipoprotein E in remnant lipoprotein metabolism involving cell surface heparan sulfate proteoglycans. J. Biol. Chem. 269: 2764-2772.
28. Ji, Z-S., H. L. Dichek, R. D. Miranda, and R. W. Mahley. 1997. Heparan sulfate proteoglycans participate in hepatic lipase- and apolipoprotein E-mediated binding and uptake of plasma lipoproteins, including high density lipoproteins. J. Biol. Chem. 272: 31285-31292.
29. Ji, Z-S., D. A. Sanan, and R. W. Mahley. 1995. Intravenous heparinase inhibits remnant lipoprotein clearance from the plasma and uptake by the liver: In vivo role of heparan sulfate proteoglycans. J. Lipid Res. 36: 583-592.
30. Ji, Z-S., R. E. Pitas, and R. W. Mahley. 1998. Differential cellular accumulation/retention of apolipoprotein E mediated by cell surface heparan sulfate proteoglycans. Apolipoproteins E3 and E2 greater than E4. J. Biol. Chem. 273: 13452-13460.
31. Fuki, I. V., K. M. Kuhn, I. R. Lomazov, V. L. Rothman, G. P. Tuszynski, R. V. Iozzo, T. L. Swenson, E. A. Fisher, and K. J. Williams. 1997. The syndecan family of proteoglycans. Novel receptors mediating internalization of atherogenic lipoproteins in vitro. J. Clin. Invest. 100: 1611-1622.
32. Williams, K. J., and I. V. Fuki. 1997. Cell-surface heparan sulfate proteoglycans: Dynamic molecules mediating ligand catabolism. Curr. Opin. Lipidol. 8: 253-262.
33. Olivecrona, T., and G. Bengtsson-Olivecrona. 1993. Lipoprotein lipase and hepatic lipase. Curr. Opin. Lipidol. 4: 187-196.
34. Lalouel, J-M., D. E. Wilson, and P-H. Iverius. 1992. Lipoprotein lipase and hepatic triglyceride lipase: Molecular and genetic aspects. Curr. Opin. Lipidol. 3: 86-95.
35. Hayden, M. R., Y. Ma, J. Brunzell, and H. E. Henderson. 1991. Genetic variants affecting human lipoprotein and hepatic lipases. Curr Opin. Lipidol. 2: 104-109.
36. Brunzell, J. D. 1995. Familial lipoprotein lipase deficiency and other causes of the chylomicronemia syndrome. In The Metabolic and Molecular Bases of Inherited Disease. 7th edition. Vol. 2. C. R. Scriver, A. L. Beaudet, W. S. Sly, and D. Valle, editors. McGraw-Hill, New York. 1913-1932.
37. Rensen, P. C. N., and T. J. C. van Berkel. 1996. Apolipoprotein E effectively inhibits lipoprotein lipase-mediated lipolysis of chylomicron-like triglyceride-rich lipid emulsions in vitro and in vivo. J. Biol. Chem. 271: 14791-14799.
38. Huang, Y., X. Q. Liu, S. C. Rall, Jr., and R. W. Mahley. 1998. Apolipoprotein E2 reduces the low density lipoprotein level in transgenic mice by impairing lipoprotein lipase-mediated lipolysis of triglyceride-rich lipoproteins. J. Biol. Chem. 273: 17483-17490.
39. Huang, Y., X. Q. Liu, S. C. Rall, Jr., J. M. Taylor, A. von Eckardstein, G. Assmann, and R. W. Mahley. 1998. Overexpression and accumulation of apolipoprotein E as a cause of hypertriglyceridemia. J. Biol. Chem. 273: 26388-26393.
40. Jong, M. C., V. E. H. Dahlmans, M. H. Hofker, and L. M. Havekes. 1997. Nascent very-low-density lipoprotein triacylglycerol hydrolysis by lipoprotein lipase is inhibited by apolipoprotein E in a dose-dependent manner. Biochem. J. 328: 745-750.
41. Gómez-Coronado, D., G. T. Sáez, M. A. Lasunción, and E. Herrera. 1993. Different hydrolytic efficiencies of adipose tissue lipoprotein lipase on very-low-density lipoprotein subfractions separated by heparin-Sepharose chromatography. Biochim. Biophys. Acta. 1167: 70-78.
42. Huang, Y., Z-S. Ji, W. J. Brecht, S. C. Rall, Jr., J. M. Taylor, and R. W. Mahley. Overexpression of apolipoprotein E3 in transgenic rabbits causes combined hyperlipidemia by stimulating hepatic very low density lipoprotein (VLDL) production and impairing VLDL lipolysis. Arterioscler. Thromb. Vasc. Biol. In press.
43. Thuren, T., K. H. Weisgraber, P. Sisson, and M. Waite. 1992. Role of apolipoprotein E in hepatic lipase catalyzed hydrolysis of phospholipid in high-density lipoproteins. Biochemistry. 31: 2332-2338.
44. Thuren, T., R. W. Wilcox, P. Sisson, and M. Waite. 1991. Hepatic lipase hydrolysis of lipid monolayers. Regulation by apolipoproteins. J. Biol. Chem. 266: 4853-4861.
45. Hamilton, R. L., S. K. Erickson, and R. J. Havel. 1995. Nascent VLDL assembly occurs in two steps in the endoplasmic reticulum (ER) of hepatocytes. In Atherosclerosis X. F. P. Woodford, J. Davignon, and A. Sniderman, editors. Elsevier Science, Amsterdam. 414-418.
46. Hamilton, R. L. 1994. Apolipoprotein-B-containing plasma lipoproteins in health and in disease. Trends Cardiovasc. Med. 4: 131-139.
47. Borén, J., S. Rustaeus, and S-O. Olofsson. 1994. Studies on the assembly of apolipoprotein B-100- and B-48-containing very low density lipoproteins in McA-RH7777 cells. J. Biol. Chem. 269: 25879-25888.
48. McLeod, R. S., Y. Zhao, S. L. Selby, J. Westerlund, and Z. Yao. 1994. Carboxyl-terminal truncation impairs lipid recruitment by apolipoprotein B100 but does not affect secretion of the truncated apolipoprotein B-containing lipoproteins. J. Biol. Chem. 269: 2852-2862.
49. Alexander, C. A., R. L. Hamilton, and R. J. Havel. 1976. Subcellular localization of B apoprotein of plasma lipoproteins in rat liver. J. Cell Biol. 69: 241-263.
50. Dixon, J. L., and H. N. Ginsberg. 1993. Regulation of hepatic secretion of apolipoprotein B-containing lipoproteins: Information obtained from cultured liver cells. J. Lipid Res. 34: 167-179.
51. Yao, Z., and R. S. McLeod. 1994. Synthesis and secretion of hepatic apolipoprotein B-containing lipoproteins. Biochim. Biophys. Acta. 1212: 152-166.
52. Raabe, M., M. M. Véniant, M. A. Sullivan, C. H. Zlot, J. Björkegren, L. B. Nielsen, J. S. Wong, R. L. Hamilton, and S. G. Young. 1999. Analysis of the role of microsomal triglyceride transfer protein in the liver of tissue-specific knockout mice. J. Clin. Invest. 103: 1287-1298.
53. Gordon, D. A., H. Jamil, D. Sharp, D. Mullaney, Z. Yao, R. E. Gregg, and J. Wetterau. 1994. Secretion of apolipoprotein B-containing lipoproteins from HeLa cells is dependent on expression of the microsomal triglyceride transfer protein and is regulated by lipid availability. Proc. Natl. Acad. Sci. USA. 91: 7628-7632.
54. Raabe, M., L. M. Flynn, C. H. Zlot, J. S. Wong, M. M. Véniant, R. L. Hamilton, and S. G. Young. 1998. Knockout of the abetalipoproteinemia gene in mice: Reduced lipoprotein secretion in heterozygotes and embryonic lethality in homozygotes. Proc. Natl. Acad. Sci. USA. 95: 8686-9691.
55. Wang, Y., R. S. McLeod, and Z. Yao. 1997. Normal activity of microsomal triglyceride transfer protein is required for the oleate-induced secretion of very low density lipoproteins containing apolipoprotein B from McA-RH7777 cells. J. Biol. Chem. 272: 12272-12278.
56. Novikoff, P. M. 1977. Fatty liver induced in Zucker "fatty" (ff) rats by a semisynthetic diet rich in sucrose. Proc. Natl. Acad. Sci. USA. 74: 3550-3554.
57. Sparks, J. D., T. L. Phung, M. Bolognino, and C. E. Sparks. 1996. Insulin-mediated inhibition of apolipoprotein B secretion requires an intracellular trafficking event and phosphatidylinositol 3-kinase activation: Studies with brefeldin A and wortmannin in primary cultures of rat hepatocytes. Biochem. J. 313: 567-574.
58. Wang, C-N., R. S. McLeod, Z. Yao, and D. N. Brindley. 1995. Effects of dexamethasone on the synthesis, degradation, and secretion of apolipoprotein B in cultured rat hepatocytes. Arterioscler. Thromb. Vasc. Biol. 15: 1481-1491.
59. van Dijk, K. W., B. J. M. van Vlijmen, H. B. van't Hof, A. van der Zee, S. Santamarina-Fojo, T. J. C. van Berkel, L. M. Havekes, and M. H. Hofker. 1999. In LDL receptor-deficient mice, catabolism of remnant lipoproteins requires a high level of apoE but is inhibited by excess apoE. J. Lipid Res. 40: 336-344.
60. Kuipers, F., M. C. Jong, Y. Lin, M. van Eck, R. Havinga, V. Bloks, H. J. Verkade, M. H. Hofker, H. Moshage, T. J. C. van Berkel, R. J. Vonk, and L. M. Havekes. 1997. Impaired secretion of very low density lipoprotein-triglycerides by apolipoprotein E-deficient mouse hepatocytes. J. Clin. Invest. 100: 2915-2922.
61. Salah, D., K. Bohnet, R. Gueguen, G. Siest, and S. Visvikis. 1997. Combined effects of lipoprotein lipase and apolipoprotein E polymorphisms on lipid and lipoprotein levels in the Stanislas cohort. J. Lipid Res. 38: 904-912.
62. Cohn, J. S., M. Tremblay, M. Amiot, D. Bouthillier, M. Roy, J. Genest, Jr., and J. Davignon. 1996. Plasma concentration of apolipoprotein E in intermediate-sized remnant-like lipoproteins in normolipidemic and hyperlipidemic subjects. Arteriocler. Thromb. Vasc. Biol. 16: 149-159.
63. Millar, J. S., J. Mayer, A. H. Lichtenstein, G. G. Dolnikowski, J. M. Ordovas, and E. J. Schaefer. 1998. Apo E and apo B100 kinetics in triglyceride-rich lipoproteins and their role in LDL production. Circulation. 98: I-305-I-306 (Abstr.).
64. Huang, Y., S. W. Schwendner, S. C. Rall, Jr., and R. W. Mahley. 1996. Hypolipidemic and hyperlipidemic phenotypes in transgenic mice expressing human apolipoprotein E2. J. Biol. Chem. 271: 29146-29151.
65. van Vlijmen, B. J. M., K. W. van Dijk, H. B. van't Hof, P. J. J. van Gorp, A. van der Zee, H. van der Boom, M. L. Breuer, M. H. Hofker, and L. M. Havekes. 1996. In the absence of endogenous mouse apolipoprotein E, apolipoprotein E*2(Arg-158→Cys) transgenic mice develop more severe hyperlipoproteinemia than apolipoprotein E*3-Leiden transgenic mice. J. Biol. Chem. 271: 30595-30602.
66. Woollett, L. A., Y. Osono, J. Herz, and J. M. Dietschy. 1995. Apolipoprotein E competitively inhibits receptor-dependent low density lipoprotein uptake by the liver but has no effect on cholesterol absorption or synthesis in the mouse. Proc. Natl. Acad. Sci. USA. 92: 12500-12504.
67. Chait, A., J. D. Brunzell, J. J. Albers, and W. R. Hazzard. 1977. Type-III hyperlipoproteinæmia ("remnant removal disease"). Insight into the pathogenetic mechanism. Lancet. 1: 1176-1178.
68. Chait, A., W. R. Hazzard, J. J. Albers, R. P. Kushwaha, and J. D. Brunzell. 1978. Impaired very low density lipoprotein and triglyceride removal in broad beta disease: Comparison with endogenous hypertriglyceridemia. Metabolism. 27: 1055-1066.
69. Ehnholm, C., R. W. Mahley, D. A. Chappell, K. H. Weisgraber, E. Ludwig, and J. L. Witztum. 1984. Role of apolipoprotein E in the lipolytic conversion of β-very low density lipoproteins to low density lipoproteins in type III hyperlipoproteinemia. Proc. Natl. Acad. Sci. USA. 81: 5566-5570.
70. Chung, B. H., and J. P. Segrest. 1983. Resistance of a very low density lipoprotein subpopulation from familial dysbetalipoproteinemia to in vitro lipolytic conversion to the low density lipoprotein density fraction. J. Lipid Res. 24: 1148-1159.
71. Huang, Y., S. C. Rall, Jr., and R. W. Mahley. 1997. Genetic factors precipitating type III hyperlipoproteinemia in hypolipidemic transgenic mice expressing human apolipoprotein E2. Arterioscler. Thromb. Vasc. Biol. 17: 2817-2824.
72. Hazzard, W. R., G. R. Warnick, G. Utermann, and J. J. Albers. 1981. Genetic transmission of isoapolipoprotein E phenotypes in a large kindred: Relationship to dysbetalipoproteinemia and hyperlipidemia. Metabolism. 30: 79-88.
73. Hopkins, P. N., L. L. Wu, M. C. Schumacher, M. Emi, R. M. Hegele, S. C. Hunt, J-M. Lalouel, and R. R. Williams. 1991. Type III dyslipoproteinemia in patients heterozygozus for familial hypercholesterolemia and apolipoprotein E2. Evidence for a gene-gene interaction. Arterioscler. Thromb. 11: 1137-1146.
74. Ma, P. T. S., T. Yamamoto, J. L. Goldstein, and M. S. Brown. 1986. Increased mRNA for low density lipoprotein receptor in livers of rabbits treated with 17α-ethinyl estradiol. Proc. Natl. Acad. Sci. USA. 83: 792-796.
75. Huang, Y., S. W. Schwendner, S. C. Rall, Jr., D. A. Sanan, and R. W. Mahley. 1997. Apolipoprotein E2 transgenic rabbits: Modulation of the type III hyperlipoproteinemic phenotype by estrogen and occurrence of spontaneous atherosclerosis. J. Biol. Chem. 272: 22685-22694.
76. Ghiselli, G., E. J. Schaefer, P. Gascon, and H. B. Brewer, Jr. 1981. Type III hyperlipoproteinemia associated with apolipoprotein E deficiency. Science. 214: 1239-1241.
77. Kurosaka, D., T. Teramoto, T. Matsushima, T. Yokoyama, A. Yamada, T. Aikawa, Y. Miyamoto, and K. Kurokawa. 1991. Apolipoprotein E deficiency with a depressed mRNA of normal size. Atherosclerosis. 88: 15-20.
78. Zhang, S. H., R. L. Reddick, J. A. Piedrahita, and N. Maeda. 1992. Spontaneous hypercholesterolemia and arterial lesions in mice lacking apolipoprotein E. Science. 258: 468-471.
79. Plump, A. S., J. D. Smith, T. Hayek, K. Aalto-Setälä, A. Walsh, J. G. Verstuyft, E. M. Rubin, and J. L. Breslow. 1992. Severe hypercholesterolemia and atherosclerosis in apolipoprotein E-deficient mice created by homologous recombination in ES cells. Cell. 71: 343-353.
80. Horie, Y., S. Fazio, J. R. Westerlund, K. H. Weisgraber, and S. C. Rall, Jr. 1992. The functional characteristics of a human apolipoprotein E variant (cysteine at residue 142) may explain its association with dominant expression of type III hyperlipoproteinemia. J. Biol. Chem. 267: 1962-1968.
81. de Knijff, P., A. M. J. M. van den Maagdenberg, A. F. H. Stalenhoef, J. A. G. Leuven, P. N. M. Demacker, L. P. Kuyt, R. R. Frants, and L. M. Havekes. 1991. Familial dysbetalipoproteinemia associated with apolipoprotein E3-Leiden in an extended multigeneration pedigree. J. Clin. Invest. 88: 643-655.
82. Ji, Z-S., S. Fazio, and R. W. Mahley. 1994. Variable heparan sulfate proteoglycan binding of apolipoprotein E variants may modulate the expression of type III hyperlipoproteinemia. J. Biol. Chem. 269: 13421-13428.
83. Wardell, M. R., S. O. Brennan, E. D. Janus, R. Fraser, and R. W. Carrell. 1987. Apolipoprotein E2-Christchurch (136 Arg→Ser). New variant of human apolipoprotein E in a patient with type III hyperlipoproteinemia. J. Clin. Invest. 80: 483-490.
84. Pocovi, M., A. Cenarro, F. Civeira, R. H. Myers, E. Casao, M. Esteban, and J. M. Ordovas. 1996. Incomplete dominance of type III hyperlipoproteinemia is associated with the rare apolipoprotein E2 (Arg136→Ser) variant in multigenerational pedigree studies. Atherosclerosis. 122: 33-46.
85. 136→Cys), a new variant of apolipoprotein E associated with incomplete dominance of type III hyperlipoproteinemia. Atherosclerosis. 109: 261 (Abstr.).
86. Walden, C. C., M. W. Huff, L. A. Leiter, P. W. Connelly, and R. A. Hegele. 1994. Detection of a new apolipoprotein-E mutation in type III hyperlipidemia using deoxyribonucleic acid restriction isotyping. J. Clin. Endocrinol. Metab. 78: 699-704.
87. Feussner, G., M. Albanese, W. A. Mann, A. Valencia, and H. Schuster. 1996. Apolipoprotein E2 (Arg-136→Gys), a variant of apolipoprotein E associated with late-onset dominance of type III hyperlipoproteinaemia. Eur. J. Clin. Invest. 26: 13-23.
88. 142→Leu) in type III hyperlipidemia. Atherosclerosis. 112: 19-28.
89. Havel, R. J., L. Kotite, J. P. Kane, P. Tun, and T. Bersot. 1983. Atypical familial dysbetalipoproteinemia associated with apolipoprotein phenotype E3/3. J. Clin. Invest. 72: 379-387.
90. Rall, S. C., Jr., Y. M. Newhouse, H. R. G. Clarke, K. H. Weisgraber, B. J. McCarthy, R. W. Mahley, and T. P. Bersot. 1989. Type III hyperlipoproteinemia associated with apolipoprotein E phenotype E3/3. Structure and genetics of an apolipoprotein E3 variant. J. Clin. Invest. 83: 1095-1101.
91. Emi, M., L. L. Wu, M. A. Robertson, R. L. Myers, R. A. Hegele, R. R. Williams, R. White, and J-M. Lalouel. 1988. Genotyping and sequence analysis of apolipoprotein E isoforms. Genomics. 3: 373-379.
92. 145→Cys). Homozygosity for two rare point mutations in the apolipoprotein E gene combined with severe type III hyperlipoproteinemia. J. Biol. Chem. 266: 10479-10484.
93. 145→Cys) is associated with incomplete dominance of type III hyperlipoproteinemia. J. Biol. Chem. 267: 13642-13646.
94. de Villiers, W. J. S., D. R. van der Westhuyzen, G. A. Coetzee, H. E. Henderson, and A. D. Marais. 1997. The apolipoprotein E2 (Arg145Cys) mutation causes autosomal dominant type III hyperlipoproteinemia with incomplete penetrance. Arterioscler. Thromb. Vasc. Biol. 17: 865-872.
95. 146→Gln), in a type III hyperlipoproteinemic subject with the E3/2 phenotype. J. Clin. Invest. 72: 1288-1297.
96. Smit, M., P. de Knijff, E. van der Kooij-Meijs, C. Groenendijk, A. M. J. M. van den Maagdenberg, J. A. Gevers Leuven, A. F. H. Stalenhoef, P. M. J. Stuyt, R. R. Frants, and L. M. Havekes. 1990. Genetic heterogeneity in familial dysbetalipoproteinemia. The E2(lys146→gln) variant results in a dominant mode of inheritance. J. Lipid Res. 31: 45-53.
97. de Knijff, P., A. M. J. M. van den Maagdenberg, D. I. Boomsma, A. F. H. Stalenhoef, A. H. M. Smelt, J. J. P. Kastelein, A. D. Marais, R. R. Frants, and L. M. Havekes. 1994. Variable expression of familial dysbetalipoproteinemia in apolipoprotein E*2(Lys146→ Gln) allele carriers. J. Clin. Invest. 94: 1252-1262.
98. Mulder, M., H. van der Boom, P. de Knijff, C. Braam, A. van den Maagdenberg, J. A. Gevers Leuven, and L. M. Havekes. 1994. Triglyceride-rich lipoproteins of subjects heterozygous for apolipoprotein E2(Lys146→Gln) are inefficiently converted to cholesterol-rich lipoproteins. Atherosclerosis. 108: 183-192.
99. Mann, W. A., N. Meyer, W. Weber, H. Greten, and U. Beisiegel. 1995. Apolipoprotein E isoforms and rare mutations: Parallel reduction in binding to cells and to heparin reflects severity of associated type III hyperlipoproteinemia. J. Lipid Res. 36: 517-525.
100. Harrisburg: a new variant of apolipoprotein E dominantly associated with type III hyperlipoproteinemia. Biochim. Biophys. Acta. 1005: 239-244.
101. Moriyama, K., J. Sasaki, A. Matsunaga, F. Arakawa, Y. Takada, K. Araki, S. Kaneko, and K. Arakawa. 1992. Apolipoprotein E1 Lys146→Gln with type III hyperlipoproteinemia. Biochim. Biophys. Acta. 1128: 58-64.
102. 146→Glu). J. Clin. Invest. 96: 1100-1107.
103. Hoffer, M. J. V., S. Niththyananthan, R. P. Naoumova, M. S. Kibirige, R. R. Frants, L. M. Havekes, and G. R. Thompson. 1996. Apolipoprotein E1-Hammersmith (Lys146→Asn;Arg147→Trp), due to a dinucleotide substitution, is associated with early manifestation of dominant type III hyperlipoproteinaemia. Atherosclerosis. 124: 183-189.
104. Wardell, M. R., K. H. Weisgraber, L. M. Havekes, and S. C. Rall, Jr. 1989. Apolipoprotein E3-Leiden contains a seven-amino acid insertion that is a tandem repeat of residues 121-127. J. Biol. Chem. 264: 21205-21210.
105. Fazio, S., Y. Horie, K. H. Weisgraber, L. M. Havekes, and S. C. Rall, Jr. 1993. Preferential association of apolipoprotein E Leiden with very low density lipoproteins of human plasma. J. Lipid Res. 34: 447-453.
106. Weisgraber, K. H., and R. W. Mahley. 1996. Human apolipoprotein E: The Alzheimer's disease connection. FASEB J. 10: 1485-1494.
107. Weisgraber, K. H. 1994. Apolipoprotein E: Structure-function relationships. Adv. Protein Chem. 45: 249-302.
108. Wilson, C., M. R. Wardell, K. H. Weisgraher, R. W. Mahley, and D. A. Agard. 1991. Three-dimensional structure of the LDL receptor-binding domain of human apolipoprotein E. Science. 252: 1817-1822.
109. Dong, L-M., S. Parkin, S. D. Trakhanov, B. Rupp, T. Simmons, K. S. Arnold, Y. M. Newhouse, T. L. Innerarity, and K. H. Weisgraber. 1996. Novel mechanism for defective receptor binding of apolipoprotein E2 in type III hyperlipoproteinemia. Nat. Struct. Biol. 3: 718-722.
110. Lalazar, A., K. H. Weisgraber, S. C. Rall, Jr., H. Giladi, T. L. Innerarity, A. Z. Levanon, J. K. Boyles, B. Amit, M. Gorecki, R. W. Mahley, and T. Vogel. 1988. Site-specific mutagenesis of human apolipoprotein E. Receptor binding activity of variants with single amino acid substitutions. J. Biol. Chem. 263: 3542-3545.
111. Innerarity, T. L., K. H. Weisgraber, K. S. Arnold, S. C. Rall, Jr., and R. W. Mahley. 1984. Normalization of receptor binding of apolipoprotein E2. Evidence for modulation of the binding site conformation. J. Biol. Chem. 259: 7261-7267.
112. Fazio, S., Y-L. Lee, Z-S. Ji, and S. C. Rall, Jr. 1993. Type III hyperlipoproteinemic phenotype in transgenic mice expressing dysfunctional apolipoprotein E. J. Clin. Invest. 92: 1497-1503.
113. van den Maagdenberg, A. M. J. M., M. H. Hofker, P. J. A. Krimpenfort, I. de Bruijn, B. van Vlijmen, H. van der Boom, L. M. Havekes, and R. R. Frants. 1993. Transgenic mice carrying the apolipoprotein E3-Leiden gene exhibit hyperlipoproteinemia. J. Biol. Chem. 268: 10540-10545.
114. van Vlijmen, B. J. M., A. M. J. M. van den Maagdenberg, M. J. J. Gijbels, H. van der Boom, H. HogenEsch, R. R. Frants, M. H. Hofker, and L. M. Havekes. 1994. Diet-induced hyperlipoproteinemia and atherosclerosis in apolipoprotein E3-Leiden transgenic mice. J. Clin. Invest. 93: 1403-1410.
115. Steinmetz, A., C. Jakobs, S. Motzny, and H. Kaffarnik. 1989. Differential distribution of apolipoprotein E isoforms in human plasma lipoproteins. Arteriosclerosis. 9: 405-411.
116. Weisgraber, K. H. 1990. Apolipoprotein E distribution among human plasma lipoproteins: Role of the cysteine-arginine interchange at residue 112. J. Lipid Res. 31: 1503-1511.
117. Kowal, R. C., J. Herz, K. H. Weisgraber, R. W. Mahley, M. S. Brown, and J. L. Goldstein. 1990. Opposing effects of apolipoproteins E and C on lipoprotein binding to low density lipoprotein receptor-related protein. J. Biol. Chem. 265: 10771-10779.
118. Mahley, R. W., and S. C. Rall, Jr. 1999. Type III hyperlipoproteinemia (dysbetalipoproteinemia): The role of apolipoprotein E in normal and abnormal lipoprotein metabolism. In The Metabolic and Molecular Bases of Inherited Disease. 8th edition. C. R. Scriver, A. L. Beaudet, W. S. Sly, and D. Valle, editors. McGraw-Hill, New York. (in press).
119. Hussain, M. M., T. L. Innerarity, W. J. Brecht, and R. W. Mahley. 1995. Chylomicron metabolism in normal, cholesterol-fed, and Watanabe heritable hvperlipidemic rabbits. Saturation of the sequestration step of the remnant clearance pathway. J. Biol. Chem. 270: 8578-8587.
120. Fazio, S., D. A. Sanan, Y-L. Lee, Z-S. Ji, R. W. Mahley, and S. C. Rall, Jr. 1994. Susceptibility to diet-induced atherosclerosis in transgenic mice expressing a dysfunctional human apolipoprotein E(Arg 112,Cys142). Arterioscler. Thromb. Vasc. Biol. 14: 1873-1879.
121. Mahley, R. W. 1985. Atherogenic lipoproteins and coronary artery disease: Concepts derived from recent advances in cellular and molecular biology. Circulation. 72: 943-948.
122. Mahley, R. W., T. L. Innerarity, S. C. Rall, Jr., and K. H. Weisgraber. 1985. Lipoproteins of special significance in atherosclerosis. Insights provided by studies of type III hyperlipoproteinemia. Ann. N.Y. Acad. Sci. 454: 209-221.
123. Mahley, R. W., T. L. Innerarity, M. S. Brown, Y. K. Ho, and J. L. Goldstein. 1980. Cholesteryl ester synthesis in macrophages: Stimulation by β-very low density lipoproteins from cholesterolfed animals of several species. J. Lipid Res. 21: 970-980.
124. Koo, C., M. E. Wernette-Hammond, Z. Garcia, M. J. Malloy, R. Uauy, C. East, D. W. Bilheimer, R. W. Mahley, and T. L. Innerarity. 1988. Uptake of cholesterol-rich remnant lipoproteins by human monocyte-derived macrophages is mediated by low density lipoprotein receptors. J. Clin. Invest. 81: 1332-1340.
125. Fujioka, Y., A. D. Cooper, and L. G. Fong. 1998. Multiple processes are involved in the uptake of chylomicron remnants by mouse peritoneal macrophages. J. Lipid Res. 39: 2339-2349.
126. Weintraub, M. S., I. Grosskopf, T. Rassin, H. Miller, G. Charach, H. H. Rotmensch, M. Liron, A. Rubinstein, and A. Iaina. 1996. Clearance of chylomicron remnants in normolipidaemic patients with coronary artery disease: Case control study over three years. Br. J. Med. 312: 935-939.
127. Weintraub, M., G. Charach, and I. Grosskopf. 1997. Disturbances in dietary fat metabolism and their role in the development of atherosclerosis. Biomed. Pharmacother. 51: 311-313.