LDL composition in E2/2 subjects and LDL distribution by Apo E genotype in type 1 diabetes


      Apo E plays an important role in chylomicron and VLDL remnant processing, uptake or conversion to LDL. The type of lipoprotein that isolates in the LDL density of E2/2 subjects was investigated and the effect of the apo E isoforms on LDL mass was determined in all genotypes in a large group of Type 1 diabetics. Analysis of the LDL composition of E2/2 homozygotes (n = 6) compared to subjects with the common E3/3 isoform (n = 6) demonstrated an enrichment in apo E, unesterified cholesterol, phospholipid and triglyceride relative to apo B in E2/2 subjects, more typical of a dense IDL remnant than of LDL. Although diabetics were studied, these findings are considered to reflect those of the general population. Comparison of the lipoprotein distribution of homozygous and heterozygous subjects revealed that, as genotype changed from E4/4 (n = 22) to E3/4 (n = 262), E3/3 (n = 710) = E2/4 (n = 30), E2/3 (n = 151), E2/2 (n = 6), LDL cholesterol decreased significantly in a stepwise manner. The decrease was not in a specific subgroup of LDL. In conclusion, for E2/2 subjects, lipoproteins isolated in the LDL density range appear to be composed mainly of dense IDL remnants and some Lp(a). The apo E isoform also has a significant effect on LDL concentration in both homozygotes and heterozygotes.


      Apo E (apolipoprotein E), DGUC (density gradient ultracentrifugation)


      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to Atherosclerosis
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Mahley R.W.
        • Huang Y.
        • Rall Jr., S.C.
        Pathogenesis of type III hyperlipoproteinemia (dysbetalipoproteinemia). Questions, quandaries, and paradoxes.
        J Lipid Res. 1999; 40: 1933-1949
        • Utermann G.
        • Langenbeck U.
        • Beisiegel U.
        • Weber W.
        Genetics of the apolipoprotein E system in man.
        Am J Hum Genet. 1980; 32: 339-347
        • Rall Jr., S.C.
        • Weisgraber K.H.
        • Mahley R.W.
        Isolation and characterization of apolipoprotein E.
        Methods Enzymol. 1986; 128: 273-287
        • Utermann G.
        Apolipoprotein E mutants, hyperlipidemia and arteriosclerosis.
        Adv Exp Med Biol. 1985; 183: 173-188
        • Rall Jr., S.C.
        • Newhouse Y.M.
        • Clarke H.R.
        • et al.
        Type III hyperlipoproteinemia associated with apolipoprotein E phenotype E3/3. Structure and genetics of an apolipoprotein E3 variant.
        J Clin Invest. 1989; 83: 1095-1101
        • Davignon J.
        • Gregg R.E.
        • Sing C.F.
        Apolipoprotein E polymorphism and atherosclerosis.
        Arteriosclerosis. 1988; 8: 1-21
        • 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 USA. 1995; 92: 12500-12504
        • 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
        • Chait A.
        • Brunzell J.D.
        • Albers J.J.
        • Hazzard W.R.
        Type-III hyperlipoproteinaemia (“remnant removal disease”). Insight into the pathogenetic mechanism.
        Lancet. 1977; 1: 1176-1178
        • 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
        • Havel R.J.
        • Kotite L.
        • Vigne J.L.
        • et al.
        Radioimmunoassay of human arginine-rich apolipoprotein, apoprotein E. Concentration in blood plasma and lipoproteins as affected by apoprotein E-3 deficiency.
        J Clin Invest. 1980; 66: 1351-1362
        • Sing C.F.
        • Davignon J.
        Role of the apolipoprotein E polymorphism in determining normal plasma lipid and lipoprotein variation.
        Am J Hum Genet. 1985; 37: 268-285
        • Ehnholm C.
        • Lukka M.
        • Kuusi T.
        • Nikkila E.
        • Utermann G.
        Apolipoprotein E polymorphism in the Finnish population: gene frequencies and relation to lipoprotein concentrations.
        J Lipid Res. 1986; 27: 227-235
        • Boerwinkle E.
        • Utermann G.
        Simultaneous effects of the apolipoprotein E polymorphism on apolipoprotein E, apolipoprotein B, and cholesterol metabolism.
        Am J Hum Genet. 1988; 42: 104-112
        • Eichner J.E.
        • Kuller L.H.
        • Ferrell R.E.
        • Meilahn E.N.
        • Kamboh M.I.
        Phenotypic effects of apolipoprotein structural variation on lipid profiles. III. Contribution of apolipoprotein E phenotype to prediction of total cholesterol, apolipoprotein B, and low density lipoprotein cholesterol in the healthy women study.
        Arteriosclerosis. 1990; 10: 379-385
        • Hallman D.M.
        • Boerwinkle E.
        • Saha N.
        • et al.
        The apolipoprotein E polymorphism: a comparison of allele frequencies and effects in nine populations.
        Am J Hum Genet. 1991; 49: 338-349
        • Xhignesse M.
        • Lussier-Cacan S.
        • Sing C.F.
        • Kessling A.M.
        • Davignon J.
        Influences of common variants of apolipoprotein E on measures of lipid metabolism in a sample selected for health.
        Arterioscler Thromb. 1991; 11: 1100-1110
        • 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
        • Winocour P.H.
        • Tetlow L.
        • Durrington P.N.
        • Ishola M.
        • Hillier V.
        • Anderson D.C.
        Apolipoprotein E polymorphism and lipoproteins in insulin-treated diabetes mellitus.
        Atherosclerosis. 1989; 75: 167-173
        • Eichner J.E.
        • Ferrell R.E.
        • Kamboh M.I.
        • et al.
        The impact of the apolipoprotein E polymorphism on the lipoprotein profile in insulin-dependent diabetes: the Pittsburgh Epidemiology of Diabetes Complications Study IX.
        Metabolism. 1992; 41: 347-351
        • Blaauwwiekel E.E.
        • Beusekamp B.J.
        • Sluiter W.J.
        • Hoogenberg K.
        • Dullaart R.P.
        Apolipoprotein E genotype is a determinant of low-density lipoprotein cholesterol and of its response to a low-cholesterol diet in Type 1 diabetic patients with elevated urinary albumin excretion.
        Diabet Med. 1998; 15: 1031-1035
        • The Diabetes Control and Complications Trial (DCCT)
        Design and methodologic considerations for the feasibility phase. The DCCT Research Group.
        Diabetes. 1986; 35: 530-545
        • The Diabetes Control and Complications Trial Research Group
        The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus.
        N Engl J Med. 1993; 329: 977-986
        • Epidemiology of Diabetes Interventions and Complications (EDIC)
        Design, implementation, and preliminary results of a long-term follow-up of the Diabetes Control and Complications Trial cohort.
        Diabetes Care. 1999; 22: 99-111
        • Warnick G.R.
        Enzymatic methods for quantification of lipoprotein lipids.
        Methods Enzymol. 1986; 129: 101-123
        • Marcovina S.M.
        • Albers J.J.
        • Wijsman E.
        • Zhang Z.
        • Chapman N.H.
        • Kennedy H.
        Differences in Lp[a] concentrations and apo[a] polymorphs between black and white Americans.
        J Lipid Res. 1996; 37: 2569-2585
        • Marcovina S.M.
        • Albers J.J.
        • Gabel B.
        • Koschinsky M.L.
        • Gaur V.P.
        Effect of the number of apolipoprotein(a) kringle 4 domains on immunochemical measurements of lipoprotein(a).
        Clin Chem. 1995; 41: 246-255
        • Hokanson J.E.
        • Austin M.A.
        • Brunzell J.D.
        Measurement and clinical significance of low-density lipoprotein subclasses.
        in: Rifai N. Warnick G.R. Dominiczak M.H. Handbook of Lipoprotein Testing. American Association of Clinical Chemistry Press, Washington1997: 267-282
        • Hixson J.E.
        • Vernier D.T.
        Restriction isotyping of human apolipoprotein E by gene amplification and cleavage with HhaI.
        J Lipid Res. 1990; 31: 545-548
        • McFarlane C.
        • Young I.S.
        • Hare L.
        • Mahon G.
        • McEneny J.
        A rapid methodology for the isolation of intermediate-density lipoprotein: characterization of lipid composition and apoprotein content.
        Clin Chim Acta. 2005; 353: 117-125
        • Eisenberg S.
        Plasma lipoprotein conversions: the origins of low-density and high-density lipoproteins.
        Ann N Y Acad Sci. 1980; 348: 30-47
        • Purnell J.Q.
        • Hokanson J.E.
        • Marcovina S.M.
        • Steffes M.W.
        • Cleary P.A.
        • Brunzell J.D.
        Effect of excessive weight gain with intensive therapy of type 1 diabetes on lipid levels and blood pressure: results from the DCCT. Diabetes Control and Complications Trial.
        Jama. 1998; 280: 140-146
        • Murdoch S.J.
        • Breckenridge W.C.
        Effect of lipid transfer proteins on lipoprotein lipase induced transformation of VLDL and HDL.
        Biochim Biophys Acta. 1996; 1303: 222-232
        • Salo M.K.
        • Rantanen R.
        • Huupponen T.
        • Lehtimaki T.
        • Jokela H.
        Apolipoprotein E phenotypes and plasma lipids in diabetic children and adolescents.
        Eur J Pediatr. 1993; 152: 564-568
        • Purnell J.Q.
        • Marcovina S.M.
        • Hokanson J.E.
        • et al.
        Levels of lipoprotein(a), apolipoprotein B, and lipoprotein cholesterol distribution in IDDM. Results from follow-up in the Diabetes Control and Complications Trial.
        Diabetes. 1995; 44: 1218-1226
        • Carr M.C.
        • Brunzell J.D.
        Abdominal obesity and dyslipidemia in the metabolic syndrome: importance of type 2 diabetes and familial combined hyperlipidemia in coronary artery disease risk.
        J Clin Endocrinol Metab. 2004; 89: 2601-2607