Apolipoprotein E and Familial Dysbetalipoproteinemia: Clinical, Biochemical, and Genetic Aspects

ABSTRACT

In humans, apolipoprotein E (apoE) is a polymorphic protein of which three common isoforms can be distinguished, designated apoE2, apoE3, and apoE4. This genetic variation is associated with different plasma lipoprotein levels, different response to diet and lipid-lowering therapy, and a variable risk for cardiovascular disease and Alzheimer's disease. An example of an apoE-mediated, autosomal recessive, lipid disorder is familial dysbetalipoproteinemia (FD), caused by mutations in the apolipoprotein E gene. Homozygosity for APOE*2 (1 in 170 persons) causes FD or type III hyperlipoproteinemia in less than 20% of the adult APOE*2 homozygotes. Less common, dominant negative mutations may also cause the disorder. The patients may present with typical skin lesions and elevated plasma levels of cholesterol and triglycerides, mainly in very-low-density lipoprotein remnants and intermediate-density lipoproteins. The disorder is associated with peripheral and coronary artery disease. Additional gene and environmental factors are necessary for the expression of this hyperlipoproteinemia. Hyperinsulinemia and defects in genes involved in the hydrolysis of triglycerides are associated with this lipid disorder. Diet and weight reduction are effective but usually not sufficient to normalize the lipid levels. Additional therapy with statins or fibrates is necessary and effective in most patients.

KEYWORDS

Familial dysbetalipoproteinemia - apolipoprotein E - apoE - remnants - type III hyperlipoproteinemia

REFERENCES

• 1 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;  276 273-281
• 2 Gofman J W, DeLalla O, Glazier F et al.. The serum lipoprotein transport system in health, metabolic disorders, atherosclerosis and coronary heart disease.  Plasma. 1954;  2 413-484
• 3 Mahley R W, Rall S C. Type III hyperlipoproteinemia (dysbetalipoproteinemia): the role of apolipoprotein E in normal and abnormal lipoprotein metabolism. In: Scriver CR, Beaudet AL, Valle D, Sly WS The Metabolic and Molecular Bases of Inherited Disease New York; McGraw-Hill 2001: 2835-2862
• 4 Paik Y K, Chang D J, Reardon C A, Davies G E, Mahley R W, Taylor J M. Nucleotide sequence and structure of the human apolipoprotein E gene.  Proc Natl Acad Sci USA. 1985;  82 3445-3449
• 5 Das H K, McPherson J, Bruns G A, Karathanasis S K, Breslow J L. Isolation, characterization, and mapping to chromosome 19 of the human apolipoprotein E gene.  J Biol Chem. 1985;  260 6240-6247
• 6 McLean J W, Elshourbagy N A, Chang D J, Mahley R W, Taylor J M. Human apolipoprotein E mRNA. cDNA cloning and nucleotide sequencing of a new variant.  J Biol Chem. 1984;  259 6498-6504
• 7 Zannis V I, McPherson J, Goldberger G, Karathanasis S K, Breslow J L. Synthesis, intracellular processing, and signal peptide of human apolipoprotein E.  J Biol Chem. 1984;  259 5495-5499
• 8 Utermann G, Hees M, Steinmetz A. Polymorphism of apolipoprotein E and occurrence of dysbetalipoproteinemia in man.  Nature. 1977;  269 604-607
• 9 Zannis V I, Just P W, Breslow J L. Human apolipoprotein E isoprotein subclasses are genetically determined.  Am J Hum Genet. 1981;  33 11-24
• 10 Zannis V I, Breslow J L. Human very low density lipoprotein apoprotein E isoprotein polymorphism is explained by genetic variation and posttranslational modification.  Biochemistry. 1981;  20 1033-1041
• 11 Weisgraber K H, Rall S CJ, Mahley R W. Human E apoprotein heterogeneity. Cysteine-arginine interchanges in the amino acid sequence of the apo-E isoforms.  J Biol Chem. 1981;  256 9077-9083
• 12 Rall S CJ, Weisgraber K H, Mahley R W. Human apolipoprotein E. The complete amino acid sequence.  J Biol Chem. 1982;  257 4171-4178
• 13 Utermann G, Pruin N, Steinmetz A. Polymorphism of apolipoprotein E. III. Effect of a single polymorphic gene locus on plasma lipid levels in man.  Clin Genet. 1979;  15 63-72
• 14 Utermann G. Morgagni lecture: genetic polymorphism of apolipoprotein E-impact on plasma lipoprotein metabolism. In: Crepaldi G, Tiengo A, Baggio G, eds Diabetes, Obesity and Hyperlipidemias Amsterdam; Elsevier 1985: 1-28
• 15 Davignon J, Gregg R E, Sing C F. Apolipoprotein E polymorphism and atherosclerosis.  Arteriosclerosis. 1988;  8 1-21
• 16 Dallongeville J, Lussier-Cacan S, Davignon J. Modulation of plasma triglyceride levels by apoE phenotype: a meta-analysis.  J Lipid Res. 1992;  33 447-454
• 17 Schaefer E J, Lamon-Fava S, Johnson S et al.. Effects of gender and menopausal status on the association of apolipoprotein E phenotype with plasma lipoprotein levels. Results from the Framingham Offspring Study.  Arterioscler Thromb. 1994;  14 1105-1113
• 18 Ordovas J M, Mooser V. The APOE locus and the pharmacogenetics of lipid response.  Curr Opin Lipidol. 2002;  13 113-117
• 19 Gerdes L U, Gerdes C, Kervinen K et al.. The apolipoprotein epsilon4 allele determines prognosis and the effect on prognosis of simvastatin in survivors of myocardial infarction: a substudy of the Scandinavian Simvastatin Survival Study.  Circulation. 2000;  101 1366-1371
• 20 Woollett L A, Osono Y, Herz J, Dietschy J M. 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 U S A. 1995;  92 12500-12504
• 21 Chait A, Hazzard W R, Albers J J, Kushwaha R P, Brunzell J D. Impaired very low density lipoprotein and triglyceride removal in broad beta disease: comparison with endogenous hypertriglyceridemia.  Metabolism. 1978;  27 1055-1066
• 22 Ehnholm C, Mahley R W, Chappell D A, Weisgraber K H, Ludwig E, Witztum J L. Role of apolipoprotein E in the lipolytic conversion of beta-very low density lipoproteins to low density lipoproteins in type III hyperlipoproteinemia.  Proc Natl Acad Sci U S A. 1984;  81 5566-5570
• 23 Demant T, Bedford D, Packard C J, Shepherd J. Influence of apolipoprotein E polymorphism on apolipoprotein B-100 metabolism in normolipemic subjects.  J Clin Invest. 1991;  88 1490-1501
• 24 Kuipers F, Jong M C, Lin Y et al.. Impaired secretion of very low density lipoprotein-triglycerides by apolipoprotein E-deficient mouse hepatocytes.  J Clin Invest. 1997;  100 2915-2922
• 25 Huang Y, Liu X Q, Rall S CJ, Mahley R W. Apolipoprotein E2 reduces the low density lipoprotein level in transgenic mice by impairing lipoprotein lipase-mediated lipolysis of triglyceride-rich lipoproteins.  J Biol Chem. 1998;  273 17483-17490
• 26 De Beer F, Stalenhoef A FH, Hoogerbrugge N et al.. Expression of type III hyperlipoproteinemia in apolipoprotein E2 (Arg158→Cys) homozygotes is associated with hyperinsulinemia.  Arterioscler Thromb Vasc Biol. 2002;  22 294-299
• 27 Mahley R W, Huang Y. Apolipoprotein E: from atherosclerosis to Alzheimer's disease and beyond.  Curr Opin Lipidol. 1999;  10 207-217
• 28 Curtiss L K, Boisvert W A. Apolipoprotein E and atherosclerosis.  Curr Opin Lipidol. 2000;  11 243-251
• 29 Mahley R W. Apolipoprotein E: cholesterol transport protein with expanding role in cell biology.  Science. 1988;  240 622-630
• 30 Rensen P CN, van Berkel T JC. Apolipoprotein E effectively inhibits lipoprotein lipase-mediated lipolysis of chylomicron-like triglyceride-rich lipid emulsions in vitro and in vivo.  J Biol Chem. 1996;  271 14791-14799
• 31 Jong M C, Dahlmans V EH, Hofker M H, Havekes L M. Nascent very-low-density lipoprotein triacylglycerol hydrolysis by lipoprotein lipase is inhibited by apolipoprotein E in a dose-dependent manner.  Biochem J. 1997;  328 745-750
• 32 Huang Y, Liu X Q, Rall S C et al.. Overexpression and accumulation of apolipoprotein E as a cause of hypertriglyceridemia.  J Biol Chem. 1998;  273 26388-26393
• 33 Willems van Dijk K, Van Vlijmen B JM, Van 't Hof H B et al.. In LDL receptor-deficient mice, catabolism of remnant lipoproteins requires a high level of apoE but is inhibited by excess apoE.  J Lipid Res. 1999;  40 336-344
• 34 Chung B H, Segrest J P. 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. 1983;  24 1148-1159
• 35 Ji Z S, Fazio S, Mahley R W. Variable heparan sulfate proteoglycan binding of apolipoprotein E variants may modulate the expression of type III hyperlipoproteinemia.  J Biol Chem. 1994;  269 13421-13428
• 36 Schwiegelshohn B, Presley J F, Gorecki M et al.. Effects of apoprotein E on intracellular metabolism of model triglyceride-rich particles are distinct from effects on cell particle uptake.  J Biol Chem. 1995;  270 1761-1769
• 37 Chen C M, Al-Haideri M, Presley J F et al.. Apoprotein E on model triglyceride-rich particles, in comparison to apoprotein B on LDL, remains relatively intact after cell uptake.  Circulation. 1995;  92 I-691
• 38 Rensen P C, Jong M C, van Vark L C et al.. Apolipoprotein E is resistant to intracellular degradation in vitro and in vivo. Evidence for retroendocytosis.  J Biol Chem. 2000;  275 8564-8571
• 39 Horsburgh K, McCarron M O, White F, Nicoll J A. The role of apolipoprotein E in Alzheimer's disease, acute brain injury and cerebrovascular disease: evidence of common mechanisms and utility of animal models.  Neurobiol Aging. 2000;  21 245-255
• 40 Prior R, Wihl G, Urmoneit B. Apolipoprotein E, smooth muscle cells and the pathogenesis of cerebral amyloid angiopathy: the potential role of impaired cerebrovascular A beta clearance.  Ann N Y Acad Sci. 2000;  903 180-186
• 41 Farrer L A, Cupples L A, Haines J L et al.. Effects of age, sex, and ethnicity on the association between apolipoprotein E genotype and Alzheimer disease. A meta-analysis. APOE and Alzheimer Disease Meta Analysis Consortium.  JAMA. 1997;  278 1349-1354
• 42 Ji Z S, Miranda R D, Newhouse Y M, Weisgraber K H, Huang Y, Mahley R W. Apolipoprotein E4 potentiates amyloid beta peptide-induced lysosomal leakage and apoptosis in neuronal cells.  J Biol Chem. 2002;  277 21821-21828
• 43 Bullido M J, Artiga M J, Recuero M et al.. A polymorphism in the regulatory region of APOE associated with risk for Alzheimer's dementia.  Nat Genet. 1998;  18 69-71
• 44 Lambert J C, Pasquier F, Cottel D, Frigard B, Amouyel P, Chartier-Harlin M C. A new polymorphism in the APOE promoter associated with risk of developing Alzheimer's disease.  Hum Mol Genet. 1998;  7 533-540
• 45 Lambert J C, Berr C, Pasquier F et al.. Pronounced impact of Th1/E47cs mutation compared with -491 AT mutation on neural APOE gene expression and risk of developing Alzheimer's disease.  Hum Mol Genet. 1998;  7 1511-1516
• 46 Brewer H B, Zech L A, Gregg R E, Schwartz D, Schaefer E J. Type III hyperlipoproteinemia: diagnosis, molecular defects, pathology, and treatment.  Ann Intern Med. 1983;  98 623-640
• 47 Morganroth J, Levy R I, Fredrickson D S. The biochemical, clinical, and genetic features of type III hyperlipoproteinemia.  Ann Intern Med. 1975;  82 158-174
• 48 Hazzard W R, O'Donnell T F, Lee Y L. Broad-beta disease (type III hyperlipoproteinemia) in a large kindred. Evidence for a monogenic mechanism.  Ann Intern Med. 1975;  82 141-149
• 49 Mishkel M A, Nazir D J, Crowther S. A longitudinal assessment of lipid ratios in the diagnosis of type III hyperlipoproteinaemia.  Clin Chim Acta. 1975;  58 121-136
• 50 Fainaru M, Mahley R W, Hamilton R L, Innerarity T L. Structural and metabolic heterogeneity of beta-very low density lipoproteins from cholesterol-fed dogs and from humans with type III hyperlipoproteinemia.  J Lipid Res. 1982;  23 702-714
• 51 Kane J P, Chen G C, Hamilton R L, Hardman D A, Malloy M J, Havel R J. Remnants of lipoproteins of intestinal and hepatic origin in familial dysbetalipoproteinemia.  Arteriosclerosis. 1983;  3 47-56
• 52 Innerarity T L, Weisgraber K H, Arnold K S, Rall Jr S C, Mahley R W. Normalization of receptor binding of apolipoprotein E2. Evidence for modulation of the binding site conformation.  J Biol Chem. 1984;  259 7261-7267
• 53 Weisgraber K H, Innerarity T L, Mahley R W. Abnormal lipoprotein receptor-binding activity of the human E apoprotein due to cysteine-arginine interchange at a single site.  J Biol Chem. 1982;  257 2518-2521
• 54 Havel R J, Chao Y, Windler E E, Kotite L, Guo L S. Isoprotein specificity in the hepatic uptake of apolipoprotein E and the pathogenesis of familial dysbetalipoproteinemia.  Proc Natl Acad Sci U S A. 1980;  77 4349-4353
• 55 Dong L M, Parkin S, Trakhanov S D et al.. Novel mechanism for defective receptor binding of apolipoprotein E2 in type III hyperlipoproteinemia.  Nat Struct Biol. 1996;  3 718-722
• 56 Mahley R W, Huang Y, Rall S CJ. Pathogenesis of type III hyperlipoproteinemia (dysbetalipoproteinemia). Questions, quandaries, and paradoxes.  J Lipid Res. 1999;  40 1933-1949
• 57 Sijbrands E J, Hoffer M J, Meinders A E et al.. Severe hyperlipidemia in apolipoprotein E2 homozygotes due to a combined effect of hyperinsulinemia and an SstI polymorphism.  Arterioscler Thromb Vasc Biol. 1999;  19 2722-2729
• 58 Olefsky J M, Farquhar J W, Reaven G M. Reappraisal of the role of insulin in hypertriglyceridemia.  Am J Med. 1974;  57 551-560
• 59 Haffner S M, Valdez R A, Hazuda H P, Mitchell B D, Morales P A, Stern M P. Prospective analysis of the insulin-resistance syndrome (syndrome X).  Diabetes. 1992;  41 715-722
• 60 Bruce R, Godsland I, Walton C, Crook D, Wynn V. Associations between insulin sensitivity, and free fatty acid and triglyceride metabolism independent of uncomplicated obesity.  Metabolism. 1994;  43 1275-1281
• 61 Taghibiglou C, Carpentier A, Van Iderstine S C et al.. Mechanisms of hepatic very low density lipoprotein overproduction in insulin resistance. Evidence for enhanced lipoprotein assembly, reduced intracellular ApoB degradation, and increased microsomal triglyceride transfer protein in a fructose-fed hamster model.  J Biol Chem. 2000;  275 8416-8425
• 62 Pollare T, Vessby B, Lithell H. Lipoprotein lipase activity in skeletal muscle is related to insulin sensitivity.  Arterioscler Thromb. 1991;  11 1192-1203
• 63 Chen M, Breslow J L, Li W, Leff T. Transcriptional regulation of the apoC-III gene by insulin in diabetic mice: correlation with changes in plasma triglyceride levels.  J Lipid Res. 1994;  35 1918-1924
• 64 Li W W, Dammerman M M, Smith J D, Metzger S, Breslow J L, Leff T. Common genetic variation in the promoter of the human apo CIII gene abolishes regulation by insulin and may contribute to hypertriglyceridemia.  J Clin Invest. 1995;  96 2601-2605
• 65 Hazzard W R, Warnick G R, Utermann G, Albers J J. Genetic transmission of isoapolipoprotein E phenotypes in a large kindred: relationship to dysbetalipoproteinemia and hyperlipidemia.  Metabolism. 1981;  30 79-88
• 66 Feussner G, Piesch S, Dobmeyer J, Fischer C. Genetics of type III hyperlipoproteinemia.  Genet Epidemiol. 1997;  14 283-297
• 67 Zhang H, Reymer P W, Liu M S et al.. Patients with apoE3 deficiency (E2/2, E3/2, and E4/2) who manifest with hyperlipidemia have increased frequency of an Asn291→Ser mutation in the human LPL gene.  Arterioscler Thromb Vasc Biol. 1995;  15 1695-1703
• 68 Hoffer M JV, Sijbrands E JG, De Man F HAF, Havekes L M, Smelt A HM, Frants R R. Increased risk for endogenous hypertriglyceridemia is associated with an apolipoprotein C3 haplotype specified by the SstI polymorphism.  Eur J Clin Invest. 1998;  28 807-812
• 69 De Knijff P, Van den Maagdenberg A M, Frants R R, Havekes L M. Genetic heterogeneity of apolipoprotein E and its influence on plasma lipid and lipoprotein levels.  Hum Mutat. 1994;  4 178-194
• 70 Havekes L, de Wit E, Leuven J G et al.. Apolipoprotein E3-Leiden. A new variant of human apolipoprotein E associated with familial type III hyperlipoproteinemia.  Hum Genet. 1986;  73 157-163
• 71 De Knijff P, Van den Maagdenberg A M, Stalenhoef A F et al.. Familial dysbetalipoproteinemia associated with apolipoprotein E3-Leiden in an extended multigeneration pedigree.  J Clin Invest. 1991;  88 643-655
• 72 Van den Maagdenberg A M, De Knijff P, Stalenhoef A F, Gevers Leuven J A, Havekes L M, Frants R R. Apolipoprotein E*3-Leiden allele results from a partial gene duplication in exon 4.  Biochem Biophys Res Commun. 1989;  165 851-857
• 73 Wardell M R, Weisgraber K H, Havekes L M, Rall S C. Apolipoprotein E3-Leiden contains a seven-amino acid insertion that is a tandem repeat of residues 121-127.  J Biol Chem. 1989;  264 21205-21210
• 74 Havekes L M, Gevers Leuven J A, van Corven E, De Wit E, Emeis J J. Functionally inactive apolipoprotein E3 in a type III hyperlipoproteinaemic patient.  Eur J Clin Invest. 1984;  14 7-11
• 75 Dong L M, Innerarity T L, Arnold K S, Newhouse Y M, Weisgraber K H. The carboxyl terminus in apolipoprotein E2 and the seven amino acid repeat in apolipoprotein E-Leiden: role in receptor-binding activity.  J Lipid Res. 1998;  39 1173-1180
• 76 Rall S C, Weisgraber K H, Innerarity T L, Bersot T P, Mahley R W. Identification of a new structural variant of human apolipoprotein E, E2(Lys146→Gln), in a type III hyperlipoproteinemic subject with the E3/E2 phenotype.  J Clin Invest. 1983;  72 1288-1297
• 77 Smit M, De Knijff P, Van der Kooij Meijs E et al.. Genetic heterogeneity in familial dysbetalipoproteinemia. The E2(Lys146→Gln) variant results in a dominant mode of inheritance.  J Lipid Res. 1990;  31 45-53
• 78 De Knijff P, Van den Maagdenberg A M, Boomsma D I et al.. Variable expression of familial dysbetalipoproteinemia in apolipoprotein E*2 (Lys146→Gln) allele carriers.  J Clin Invest. 1994;  94 1252-1262
• 79 Mulder M, Van der Boom H, De Knijff P et al.. Triglyceride-rich lipoproteins of subjects heterozygous for apolipoprotein E2(Lys146→Gln) are inefficiently converted to cholesterol-rich lipoproteins.  Atherosclerosis. 1994;  108 183-192
• 80 Chappell D A. High receptor binding affinity of lipoproteins in atypical dysbetalipoproteinemia (type III hyperlipoproteinemia).  J Clin Invest. 1989;  84 1906-1915
• 81 De Man F HAF, De Beer F, Van der Laarse A, Smelt A HM, Gevers Leuven J A, Havekes L M. Effect of apolipoprotein E variants on lipolysis of very low density lipoproteins by heparan sulphate proteoglycan-bound lipoprotein lipase.  Atherosclerosis. 1998;  136 255-262
• 82 de Beer F, van Dijk K W, Jong M C et al.. Apolipoprotein E2 (Lys 146-Gln) causes hypertriglyceridemia due to an apolipoprotein E variant-specific inhibition of lipolysis of very low density lipoproteins-triglycerides.  Arterioscler Thromb Vasc Biol. 2000;  20 1800-1806
• 83 Dallongeville J, Boulet J, Davignon J, Lussier-Cacan S. Fish oil supplementation reduces β-very low density lipoprotein in type III hyperlipoproteinemia.  Arterioscler Thromb. 1991;  11 864-871
• 84 Hoogwerf B J, Bantle J P, Kuba K, Frantz I D, Hunninghake D M. Treatment of type III hyperlipoproteinemia with four different treatment regimens.  Atherosclerosis. 1984;  51 251-259
• 85 Zhao S P, Smelt A HM, Gevers Leuven J A, Vroom T FFP, Van der Laarse A, Van 't Hooft F M. Changes of lipoprotein profile in familial dysbetalipoproteinemia with gemfibrozil.  Am J Med. 1994;  96 49-56
• 86 Larsen M L, Illingworth D R, O’Malley J P. Comparative effects of gemfibrozil and clofibrate in type III hyperlipoproteinemia.  Atherosclerosis. 1994;  106 235-240
• 87 Feussner G, Eichinger M, Ziegler R. The influence of simvastatin alone or in combination with gemfibrozil on plasma lipids and lipoproteins in patients with type III hyperlipidemia.  Clin Investig. 1992;  70 1027-1035
• 88 Van Dam M, Zwart M, De Beer F et al.. Long term efficacy and safety of atorvastatin in the treatment of severe type III and combined dyslipidaemia.  Heart. 2002;  88 234-238
• 89 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;  87 517-525
• 90 Stuyt P M, Demacker P N, Van ‘t Laar A. A study of the hypolipidemic effect of estrogen in type III hyperlipoproteinemia.  Horm Metab Res. 1986;  18 607-610
• 91 De Beer F, Smelt A HM, Van Vark L C, Hoogerbrugge N, Havekes L M, Gevers Leuven J A. The effect of tibolone on the lipoprotein profile of postmenopausal women with type III hyperlipoproteinemia.  J Intern Med. 2002;  251 148-155