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Effect of apolipoprotein E and insulin resistance on VLDL particles in combined hyperlipidemic patients

      Abstract

      Apolipoprotein (apo) E2 and high insulin levels are associated with the severity of hypertriglyceridemia in patients with combined hyperlipidemia. To study how these determinants affect very low-density lipoprotein (VLDL) in combined hyperlipidemic patients, we characterized VLDL particles in 106 unrelated patients with combined hyperlipidemia. The study was performed after 9 weeks of standardized dietary intake and after an overnight fast. Patients heterozygous for apoE2 had significantly higher mean levels of VLDL cholesterol by 0.71 mmol/l (95% CI, 0.30 to 1.12 mmol/l, P < 0.005) and VLDL triglycerides by 0.88 mmol/l (95% CI, 0.30 to 1.47 mmol/l, P < 0.005) compared to patients without apoE2. The VLDL triglyceride content per particle and the calculated diameter of the VLDL particles were similar in both groups, which indicate a higher number of circulating VLDL particles in heterozygous apoE2 carriers. Patients with high fasting insulin levels (≥ 80 pmol/l) had a higher mean serum VLDL triglyceride level by 0.56 mmol/l (95% CI, 0.04 to 1.07 mmol/l, P < 0.05). The calculated VLDL diameter was larger by 3.7 nm (95% CI, 1.2 to 6.2 nm, P < 0.005) and the particles contained more triglycerides by 2.7 weight percent (95% CI, 0.3 to 5.1 weight percent, P < 0.05). These insulin-dependent changes in VLDL particles were only present in the absence of apoE2. In conclusion, patients heterozygous for apoE2 have higher numbers of circulating VLDL particles, whereas patients with high fasting insulin levels have larger, triglyceride enriched VLDL particles.

      Keywords

      Abbreviations:

      Apo = apolipoprotein (), CI = confidence interval (), HDL = high-density lipoprotein (), LDL = intermediate-density (), lipoprotein (), LDL = low-density lipoprotein (), VLDL = very low-density lipoprotein ()
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      References

        • Sijbrands EJG
        • Westendorp RGJ
        • Hoffer MJV
        • Havekes LM
        • Frants RR
        • Meinders AE
        • Frölich M
        • Smelt AHM
        Effect of insulin resistance, apoE2 allele, and smoking on combined hyperlipidemia.
        Arterioscler Thromb. 1994; 14: 1576-1580
        • Mahley RW
        • Apolipoprotein E
        Cholesterol transport protein with expanding role in cell biology.
        Science. 1988; 240: 622-630
        • Davignon J
        • Gregg RE
        • Sing CF
        Apolipoprotein E polymorphism and atherosclerosis.
        Arteriosclerosis. 1988; 8: 1-21
        • Demant T
        • Bedford D
        • Packard CJ
        • Shepherd J
        Influence of apolipoprotein E polymorphism on apolipoprotein B-100 metabolism in normolipemic subjects.
        J Clin Invest. 1991; 88: 1490-1501
        • Weisgraber KH
        • Innerarity TL
        • Mahley RW
        Abnormal lipoprotein receptor-binding activity of the human E apo-protein due to cysteine-arginine interchange at a single site.
        J Biol Chem. 1982; 257: 2518-2521
        • Innerarity TL
        • Weisgraber KH
        • Arnold KS
        • Rall Jr, SC
        • Mahley RW
        Normalization of receptor binding of apolipoprotein E2. Evidence for modulation of the binding site conformation.
        J Biol Chem. 1984; 259: 7261-7267
        • Kowal RC
        • Herz J
        • Weisgraber KH
        • Mahley RW
        • Brown MS
        • Goldstein JL
        Opposing effects of apolipoproteins E and C on lipoprotein binding to low density lipoprotein receptor-related protein.
        J Biol Chem. 1990; 265: 10771-10779
        • Brown AJ
        • Roberts DC
        The effect of fasting triacylglyceride concentration and apolipoprotein E polymorphism on postprandial lipemia.
        Arterioscler Thromb. 1991; 11: 1737-1744
        • Brown MS
        • Kovanen PT
        • Goldstein JL
        Regulation of plasma cholesterol by lipoprotein receptors.
        Science. 1981; 212: 628-635
        • Kuyl JM
        • Mendelsohn D
        Observed relationship between ratios HDL-cholesterol/total cholesterol and apolipo-protein A1/apolipoprotein B.
        Clin Chem. 1992; 25: 313-316
        • Reaven GM
        • Lerner RL
        • Stern MP
        • Farquhar JW
        Role of insulin in endogenous hypertriglyceridemia.
        J Clin Invest. 1967; 46: 1756-1767
        • Glueck CJ
        • Levy RI
        • Fredrickson DS
        Immunoreactive insulin, glucose tolerance, and carbohydrate inducibility in types II, III, IV, and V hyperlipoproteinemia.
        Diabetes. 1969; 18: 739-747
        • Abbott WG
        • Lillioja S
        • Young AA
        • Zawadzki JK
        • Yki Jarvinen H
        • Christin L
        • Howard BV
        Relationships between plasma lipoprotein concentrations and insulin action in an obese hyperinsulinemic population.
        Diabetes. 1987; 36: 897-904
        • Garg A
        • Helderman JH
        • Koffler M
        • Ayuso R
        • Rosenstock J
        • Raskin P
        Relationship between lipoprotein levels and in vivo insulin action in normal young white men.
        Metabolism. 1988; 37: 982-987
        • Laakso M
        • Sarlund H
        • Mykkanen L
        Insulin resistance is associated with lipid and lipoprotein abnormalities in subjects with varying degrees of glucose tolerance.
        Arteriosclerosis. 1990; 10: 223-231
        • Karhapää P
        • Voutilainen E
        • Malkki M
        • Laakso M
        Obese men with type IIb hyperlipidemia are insulin resistant.
        Arterioscler Thromb. 1993; 13: 1469-1475
        • Wiggins D
        • Gibbons GF
        The lipolysis/esterification cycle of hepatic triacylglycerol. Its role in the secretion of very-low-density lipoprotein and its response to hormones and sulphonylureas.
        Biochem J. 1992; 284: 457-462
        • Howard BV
        • Abbott WG
        • Egusa G
        • Taskinen MR
        Coordination of very low-density lipoprotein triglyceride and apolipoprotein B metabolism in humans: effects of obesity and non-insulin-dependent diabetes mellitus.
        Am Heart J. 1987; 113: 522-526
        • Yki-Jarvinen H
        • Taskinen MR
        Interrelationships among insulin's antilipolytic and glucoregulatory effects and plasma triglycerides in nondiabetic and diabetic patients with endogenous hypertriglyceridemia.
        Diabetes. 1988; 37: 1271-1278
        • CastroCabezas M
        • De Bruin TW
        • De Valk HW
        • Shoulders CC
        • Jansen H
        Impaired fatty acid metabolism in familial combined hyperlipidemia. A mechanism associating hepatic apolipoprotein B overproduction and insulin resistance.
        J Clin Invest. 1993; 92: 160-168
      1. Anonymous. Report of the National Cholesterol Education Program Expert Panel on detection, evaluation, and treatment of high blood cholesterol in adults. Arch Intern Med 1988;148:36–69.

        • Wijsman BP
        • Adrichem CM
        • Van't Hooft FM
        • Gevers Leuven JA
        • Van der Laarse A
        • Smelt AHM
        Diverse effects of the Dutch guidelines for a healthy diet on serum lipids of male patients with type IIa and type IIb hyperlipoproteinemia.
        Eur J Int Med. 1993; 4: 115-122
        • Hansen PS
        • Rudiger N
        • Tybjaerg-Hansen A
        • Faergeman O
        • Gregersen N
        Detection of the apoB-3500 mutation (glutamine for arginine) by gene amplification and cleavage with MspI.
        J Lipid Res. 1991; 32: 1229-1233
        • Siedel J
        • Hägele EO
        • Ziegenhorn J
        • Wahlefeld AW
        Reagent for the enzymatic determination of serum total cholesterol with improved lipolytic efficiency.
        Clin Chem. 1983; 29: 1075-1080
        • Bucolo G
        • David H
        Quantitative determination of serum triglycerides by the use of enzymes.
        Clin Chem. 1973; 19: 475-482
        • Havel RJ
        • Eder HA
        • Bragdon JH
        The distribution and chemical composition of ultracentrifugally separated lipoproteins in human serum.
        Clin Chem. 1955; 34: 1345-1353
        • Burstein M
        • Scholnick HR
        • Morfin R
        Rapid method for the isolation of lipoproteins from human serum by precipitation with polyanions.
        J Lipid Res. 1970; 11: 583-595
        • Havekes LM
        • De Knijff P
        • Beisiegel U
        • Havinga J
        • Smit M
        • Klasen E
        A rapid micromethod for apolipoprotein E phenotyping directly in serum.
        J Lipid Res. 1987; 28: 455-463
        • Cheung MC
        • Albers JJ
        The measurement of apolipoprotein A–I and A–II levels in men and women by immunoassay.
        J Clin Invest. 1977; 60: 43-50
        • Albers JJ
        • Cabana VG
        • Hazzard WR
        Immunoassay of human plasma apolipoprotein B.
        Metabolism. 1975; 24: 1339-1351
        • Passey RB
        • Gillum RF
        • Fuller JB
        • Urry FM
        • Giles ML
        Evaluation and comparison of 10 glucose methods and the reference method recommended in the proposed product class standard.
        Clin Chem. 1977; 23: 131-139
        • Starr JI
        • Mako ME
        • Juhn D
        • Rubenstein AH
        Measurement of serum proinsulin-like material: cross-reactivity of porcine and human proinsulin in the radioimmunoassay.
        J Lab Clin Med. 1978; 91: 691-692
        • Laakso M
        How good a marker is insulin level for insulin resistance?.
        Am J Epidemiol. 1993; 137: 959-965
        • Zhao SP
        • Van den Maagdenberg AMJM
        • Vroom TFFP
        • Van't Hooft FM
        • Gevers Leuven JA
        • Havekes LM
        • Frants RR
        • Van der Laarse A
        • Smelt AHM
        Lipoprotein profiles in a family with two mutants of apolipoprotein E: possible association with hypertriglyceridemia but not with dysbetalipoproteinaemia.
        Clin Science. 1994; 86: 323-329
        • Von Stähler F
        • Gruber W
        • Stinshoff K
        • Röschlau P
        Eine praxisgerechte enzymatische Cholesterin-Bestimmung.
        Med Lab. 1977; 30: 29-37
        • Takayama M
        • Itoh S
        • Nakasaki T
        • Tanimuzu I
        A new enzymatic method for determination of serum choline-containing phospholipids.
        Clinica Chimica Acta. 1977; 79: 93-98
        • Lowry OH
        • Rosebrough NJ
        • Farr L
        • Randall RJ
        Protein measurement with folin phenol reagent.
        J Biolog Chem. 1951; 193: 265-275
        • Redgrave TG
        • Carlson LA
        Changes in plasma very low density and low density lipoprotein content, composition, and size after a fatty meal in normo- and hypertriglyceridemic man.
        J Lipid Res. 1979; 20: 217-229
        • Smit M
        • De Knijff P
        • Rosseneu M
        • Bury J
        • Klasen E
        • Frants RR
        • Havekes LM
        Apolipoprotein E polymorphism in the Netherlands and its effect on plasma lipid and apolipoprotein levels.
        Hum Genet. 1988; 80: 287-292
      2. Gardner MJ, Altman DG. Calculating confidence intervals for means and their differences. In: Gardner MJ and Altman DG. (eds). Statistics with confidence. London, UK: BMJ 1990;20–27.

        • Gregg RE
        • Zech LA
        • Schaefer EJ
        • Brewer Jr, HB
        Apolipoprotein E metabolism in normolipoproteinemic human subjects.
        J Lipid Res. 1984; 25: 1167-1176
        • Zhao SP
        • Smelt AHM
        • Gevers Leuven JA
        • Van den Maagdenberg AM
        • Van der Laarse A
        • Van't Hooft FM
        Lipoproteins in familial dysbetalipoproteinemia. Variation of serum cholesterol level associated with VLDL concentration.
        Arterioscler Thromb. 1993; 13: 316-323
        • Dallongeville J
        • Roy M
        • Leboeuf N
        • Xhignesse M
        • Davignon J
        Apolipoprotein E polymorphism association with lipoprotein profile in endogenous hypertriglyceridemia and familial hypercholesterolemia.
        Arterioscler Thromb. 1991; 11: 272-278
        • Weintraub MS
        • Eisenberg S
        • Breslow JL
        Different patterns of postprandial lipoprotein metabolism in normal, type IIa, type III, and type IV hyperlipoproteinemic individuals.
        J Clin Invest. 1987; 79: 1110-1119
        • Wilson C
        • Wardell MR
        • Weisgraber KH
        • Mahley RW
        • Agard DA
        Three-dimensional structure of the LDL receptor-binding domain of human apolipoprotein E.
        Science. 1991; 252: 1817-1822
      3. Wardell MR, Wilson C, Agard DA, Mahley RW, Weisgraber KH. Crystal structures of the common apolipoprotein E variants: insights into functional mechanisms. In: Sirtori CR, Fraceschini G and Brewer BH Jr. (eds). Human apolipoprotein mutants III. Berlin, Germany: Springer Verlag, NATO ASI Series, 1993;II 73:81–96.

        • Reaven GM
        • Chen YD
        • Jeppesen J
        • Maheux P
        • Krauss RM
        Insulin resistance and hyperinsulinemia in individuals with small, dense low density lipoprotein particles.
        J Clin Invest. 1993; 92: 141-146
      4. Rotter JI, Vadheim CM, Rimoin DL. Diabetes mellitus. In: King RA, Rotter JI and Motulski AG. (eds). The genetic basis of common diseases. NY, USA: Oxford University Press, 1992;413–481.

        • Eliasson B
        • Attvall S
        • Taskinen MR
        • Smith U
        The insulin resistance syndrome in smokers is related to smoking habits.
        Arterioscler Thromb. 1994; 14: 1946-1950
        • Rimm EB
        • Chan J
        • Stampfer MJ
        • Colditz GA
        • Willett WC
        Prospective study of cigarette smoking, alcohol use, and the risk of diabetes in men.
        Br Med J. 1995; 310: 555-559
        • Austin MA
        • Wijsman E
        • Guo SW
        • Krauss RM
        • Brunzell JD
        • Deeb S
        Lack of evidence for linkage between low-density lipoprotein subclass phenotypes and the apolipoprotein B locus in familial combined hyperlipidemia.
        Genet Epidemiol. 1991; 8: 287-297
        • Jarvik GP
        • Beaty TH
        • Gallagher PR
        • Coates PM
        • Cortner JA
        Genotype at a major locus with large effects on apolipoprotein B levels predicts familial combined hyperlipidemia.
        Genet Epidemiol. 1993; 10: 257-270
        • Jarvik GP
        • Brunzell JD
        • Austin MA
        • Krauss RM
        • Motulsky AG
        • Wijsman E
        Genetic predictors of FCHL in four large pedigrees: influence of apoB level major locus predicted genotype and LDL subclass phenotype.
        Arterioscler Thromb. 1994; 14: 1687-1704
        • Wojciechowski AP
        • Farrall M
        • Cullen P
        • Wilson TM
        • Bayliss JD
        • Farren B
        • Griffin BA
        • Caslake MJ
        • Packard CJ
        • Shepherd J
        • Thakker R
        • Scott J
        Familial combined hyperlipidaemia linked to the apolipoprotein AI-CIII-AIV gene cluster on chromosome 11q23-q24.
        Nature. 1991; 349: 161-164
        • Nishina PM
        • Johnson JP
        • Naggert JK
        • Krauss RM
        Linkage of atherogenic lipoprotein phenotype to the low density lipoprotein receptor locus on the short arm of chromosome 19.
        Proc Natl Acad Sci USA. 1992; 89: 708-712
        • Nevin DN
        • Brunzell JD
        • Deeb SS
        The LPL gene in individuals with familial combined hyperlipidemia and decreased LPL activity.
        Arterioscler Thromb. 1994; 14: 869-873