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J Clin Invest. Dec 1995; 96(6): 2601–2605.
PMCID: PMC185964

Common genetic variation in the promoter of the human apo CIII gene abolishes regulation by insulin and may contribute to hypertriglyceridemia.

Abstract

Overexpression of plasma apolipoprotein CIII (apo CIII) causes hypertriglyceridemia in transgenic mice. A genetically variant form of the human apo CIII promoter, containing five single base pair changes, has been shown to be associated with severe hypertriglyceridemia in a patient population. In animals and in cultured cells the apo CIII gene is transcriptionally downregulated by insulin. In this study we demonstrate that, unlike the wild-type promoter, the variant promoter was defective in its response to insulin treatment, remaining constitutively active at all concentrations of insulin. The loss of insulin regulation was mapped to polymorphic sites at -482 and -455, which fall within a previously identified insulin response element. Loss of insulin regulation could result in overexpression of the apo CIII gene and contribute to the development of hypertriglyceridemia. The variant apo CIII promoter is common in the human population and may represent a major contributing factor to the development of hypertriglyceridemia.

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Selected References

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  • Ito Y, Azrolan N, O'Connell A, Walsh A, Breslow JL. Hypertriglyceridemia as a result of human apo CIII gene expression in transgenic mice. Science. 1990 Aug 17;249(4970):790–793. [PubMed]
  • Aalto-Setälä K, Fisher EA, Chen X, Chajek-Shaul T, Hayek T, Zechner R, Walsh A, Ramakrishnan R, Ginsberg HN, Breslow JL. Mechanism of hypertriglyceridemia in human apolipoprotein (apo) CIII transgenic mice. Diminished very low density lipoprotein fractional catabolic rate associated with increased apo CIII and reduced apo E on the particles. J Clin Invest. 1992 Nov;90(5):1889–1900. [PMC free article] [PubMed]
  • Carlson LA, Ballantyne D. Changing relative proportions of apolipoproteins CII and CIII of very low density lipoproteins in hypertriglyceridaemia. Atherosclerosis. 1976 May-Jun;23(3):563–568. [PubMed]
  • Ginsberg HN, Le NA, Goldberg IJ, Gibson JC, Rubinstein A, Wang-Iverson P, Norum R, Brown WV. Apolipoprotein B metabolism in subjects with deficiency of apolipoproteins CIII and AI. Evidence that apolipoprotein CIII inhibits catabolism of triglyceride-rich lipoproteins by lipoprotein lipase in vivo. J Clin Invest. 1986 Nov;78(5):1287–1295. [PMC free article] [PubMed]
  • Malmendier CL, Lontie JF, Delcroix C, Dubois DY, Magot T, De Roy L. Apolipoproteins C-II and C-III metabolism in hypertriglyceridemic patients. Effect of a drastic triglyceride reduction by combined diet restriction and fenofibrate administration. Atherosclerosis. 1989 Jun;77(2-3):139–149. [PubMed]
  • Rees A, Stocks J, Sharpe CR, Vella MA, Shoulders CC, Katz J, Jowett NI, Baralle FE, Galton DJ. Deoxyribonucleic acid polymorphism in the apolipoprotein A-1-C-III gene cluster. Association with hypertriglyceridemia. J Clin Invest. 1985 Sep;76(3):1090–1095. [PMC free article] [PubMed]
  • Aalto-Setälä K, Kontula K, Sane T, Nieminen M, Nikkilä E. DNA polymorphisms of apolipoprotein A-I/C-III and insulin genes in familial hypertriglyceridemia and coronary heart disease. Atherosclerosis. 1987 Jul;66(1-2):145–152. [PubMed]
  • Taş S. Strong association of a single nucleotide substitution in the 3'-untranslated region of the apolipoprotein-CIII gene with common hypertriglyceridemia in Arabs. Clin Chem. 1989 Feb;35(2):256–259. [PubMed]
  • Ahn YI, Valdez R, Reddy AP, Cole SA, Weiss KM, Ferrell RE. DNA polymorphisms of the apolipoprotein AI/CIII/AIV gene cluster influence plasma cholesterol and triglyceride levels in the Mayans of the Yucatán Peninsula, Mexico. Hum Hered. 1991;41(5):281–289. [PubMed]
  • Zeng Q, Dammerman M, Takada Y, Matsunaga A, Breslow JL, Sasaki J. An apolipoprotein CIII marker associated with hypertriglyceridemia in Caucasians also confers increased risk in a west Japanese population. Hum Genet. 1995 Apr;95(4):371–375. [PubMed]
  • Gruber PJ, Torres-Rosado A, Wolak ML, Leff T. Apo CIII gene transcription is regulated by a cytokine inducible NF-kappa B element. Nucleic Acids Res. 1994 Jun 25;22(12):2417–2422. [PMC free article] [PubMed]
  • Staels B, Vu-Dac N, Kosykh VA, Saladin R, Fruchart JC, Dallongeville J, Auwerx J. Fibrates downregulate apolipoprotein C-III expression independent of induction of peroxisomal acyl coenzyme A oxidase. A potential mechanism for the hypolipidemic action of fibrates. J Clin Invest. 1995 Feb;95(2):705–712. [PMC free article] [PubMed]
  • Chen M, Breslow JL, 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 Nov;35(11):1918–1924. [PubMed]
  • Dammerman M, Sandkuijl LA, Halaas JL, Chung W, Breslow JL. An apolipoprotein CIII haplotype protective against hypertriglyceridemia is specified by promoter and 3' untranslated region polymorphisms. Proc Natl Acad Sci U S A. 1993 May 15;90(10):4562–4566. [PMC free article] [PubMed]
  • Reue K, Leff T, Breslow JL. Human apolipoprotein CIII gene expression is regulated by positive and negative cis-acting elements and tissue-specific protein factors. J Biol Chem. 1988 May 15;263(14):6857–6864. [PubMed]
  • Leff T, Reue K, Melian A, Culver H, Breslow JL. A regulatory element in the ApoCIII promoter that directs hepatic specific transcription binds to proteins in expressing and nonexpressing cell types. J Biol Chem. 1989 Sep 25;264(27):16132–16137. [PubMed]
  • Dignam JD, Lebovitz RM, Roeder RG. Accurate transcription initiation by RNA polymerase II in a soluble extract from isolated mammalian nuclei. Nucleic Acids Res. 1983 Mar 11;11(5):1475–1489. [PMC free article] [PubMed]
  • Kulozik AE, Bellan-Koch A, Bail S, Kohne E, Kleihauer E. Thalassemia intermedia: moderate reduction of beta globin gene transcriptional activity by a novel mutation of the proximal CACCC promoter element. Blood. 1991 May 1;77(9):2054–2058. [PubMed]
  • Smith JD, Brinton EA, Breslow JL. Polymorphism in the human apolipoprotein A-I gene promoter region. Association of the minor allele with decreased production rate in vivo and promoter activity in vitro. J Clin Invest. 1992 Jun;89(6):1796–1800. [PMC free article] [PubMed]
  • Reijnen MJ, Sladek FM, Bertina RM, Reitsma PH. Disruption of a binding site for hepatocyte nuclear factor 4 results in hemophilia B Leyden. Proc Natl Acad Sci U S A. 1992 Jul 15;89(14):6300–6303. [PMC free article] [PubMed]
  • Koivisto UM, Palvimo JJ, Jänne OA, Kontula K. A single-base substitution in the proximal Sp1 site of the human low density lipoprotein receptor promoter as a cause of heterozygous familial hypercholesterolemia. Proc Natl Acad Sci U S A. 1994 Oct 25;91(22):10526–10530. [PMC free article] [PubMed]
  • Reaven GM, Mondon CE, Chen YD, Breslow JL. Hypertriglyceridemic mice transgenic for the human apolipoprotein C-III gene are neither insulin resistant nor hyperinsulinemic. J Lipid Res. 1994 May;35(5):820–824. [PubMed]
  • Ogami K, Hadzopoulou-Cladaras M, Cladaras C, Zannis VI. Promoter elements and factors required for hepatic and intestinal transcription of the human ApoCIII gene. J Biol Chem. 1990 Jun 15;265(17):9808–9815. [PubMed]
  • O'Brien RM, Bonovich MT, Forest CD, Granner DK. Signal transduction convergence: phorbol esters and insulin inhibit phosphoenolpyruvate carboxykinase gene transcription through the same 10-base-pair sequence. Proc Natl Acad Sci U S A. 1991 Aug 1;88(15):6580–6584. [PMC free article] [PubMed]

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