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Thromb Haemost 2003; 90(01): 43-51
DOI: 10.1055/s-0037-1613597
Blood Coagulation, Fibrinolysis and Cellular Haemostasis
Schattauer GmbH

Oxysterols suppress constitutive fibrinogen expression

Hui Xia
1   Lindsley F Kimball Research Institute of the New York Blood Center, New York, USA
,
Colvin M. Redman
1   Lindsley F Kimball Research Institute of the New York Blood Center, New York, USA
› Author AffiliationsFinancial support: Supported by the American Heart Association (Grant in Aid, 0150045N) and the Kirby Foundation.
Further Information

Publication History

Received 30 December 2002

Accepted after revision 25 February 2003

Publication Date:
07 December 2017 (online)

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Summary

Elevated levels of both fibrinogen and cholesterol are risk factors in coronary artery disease. Previously we reported a metabolic link between fibrinogen and lipid metabolism in that HepG2 cells that were programmed by transfection of Bβ-fibrinogen cDNA to overexpress fibrinogen exhibited increased synthesis of cholesterol and increased secretion of apolipoprotein B. In this study we demonstrate that oxysterols, which participate in maintaining cholesterol homeostasis, also down regulate fibrinogen expression. Treatment of HepG2 cells with 25-hydroxycholesterol lowered fibrinogen Aα, Bβ and γ mRNA levels and inhibited fibrinogen synthesis and secretion but had no effect on α1-antitrypsin which, like fibrinogen, is an acute-phase protein. The inhibition of fibrinogen synthesis by oxysterols was maintained in interleukin-6 treated cells. Other oxysterols, that inhibit cholesterol synthesis by a feedback mechanism, also diminished fibrinogen expression in HepG2, rat H-4-II-E hepatoma cells and in primary human hepatocytes. Overexpression of SREBP-1 and SREBP-2 by transfection of HepG2 cells, or treatment with a synthetic LXRα agonist, which affect cholesterol metabolism, did not affect fibrinogen expression. We conclude that fibrinogen and cholesterol may share a novel common regulatory pathway.

Keywords

Fibrinogen - cholesterol - oxysterols
 

  • References

  • 1 Wilhelmsen L, Svardsudd K, Korsan-Bengtsen K, Larsson B, Welin L, Tibblin G. Fibrinogen as a risk factor for stroke and myocardial infarction. N Engl J Med 1984; 311: 501-5.
    CrossrefPubMedGoogle Scholar
  • 2 Kannel WB, Wolf PA, Castelli WP, D’Agostino RB. Fibrinogen and risk of cardiovascular disease. The Framingham Study. JAMA 1987; 258: 1183-6.
    CrossrefPubMedGoogle Scholar
  • 3 Ernst E. Plasma fibrinogen—an independent cardiovascular risk factor. [Review. J Intern Med 1990; 227: 365-72.
    CrossrefPubMedGoogle Scholar
  • 4 Qizilbash N, Jones L, Warlow C, Mann J. Fibrinogen and lipid concentrations as risk factors for transient ischaemic attacks and minor ischaemic strokes. BMJ 1991; 303: 605-9.
    CrossrefPubMedGoogle Scholar
  • 5 Banerjee AK, Pearson J, Gilliland EL, Goss D, Lewis JD, Stirling Y, Meade TW. A six year prospective study of fibrinogen and other risk factors associated with mortality in stable claudicants. Thromb Haemost 1992; 68: 261-3.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 6 Ernst E, Resch KL. Fibrinogen as a cardiovascular risk factor: A meta-analysis and review of the literature. Ann Intern Med 1993; 118: 956-63.
    CrossrefPubMedGoogle Scholar
  • 7 Lind P, Hedblad B, Stavenow L, Janzon L, Eriksson KF, Lindgarde F. Influence of plasma fibrinogen levels on the incidence of myocardial infarction and death is modified by other inflammation-sensitive proteins: a long-term cohort study. Arterioscler Thromb Vasc Biol 2001; 21: 452-8.
    CrossrefPubMedGoogle Scholar
  • 8 Xia H, Redman C. Enhanced secretion of ApoB by transfected HepG2 cells overex-pressing fibrinogen. Biochem Biophys Res Commun 2000; 273: 377-84.
    CrossrefPubMedGoogle Scholar
  • 9 Goldstein JL, Brown MS. Regulation of the mevalonate pathway. Nature 1990; 343: 425-30.
    CrossrefPubMedGoogle Scholar
  • 10 Bennett MK, Lopez JM, Sanchez HB, Osborne TF. Sterol regulation of fatty acid synthase promoter. Coordinate feedback regulation of two major lipid pathways. J Biol Chem 1995; 270: 25578-83.
    CrossrefPubMedGoogle Scholar
  • 11 Willy PJ, Umesono K, Ong ES, Evans RM, Heyman RA, Mangelsdorf DJ. LXR, a nuclear receptor that defines a distinct retinoid response pathway. Genes Dev 1995; 9: 1033-45.
    CrossrefPubMedGoogle Scholar
  • 12 Janowski BA, Willy PJ, Devi TR, Falck JR, Mangelsdorf DJ. An oxysterol signalling pathway mediated by the nuclear receptor LXR alpha. Nature 1996; 383: 728-31.
    CrossrefPubMedGoogle Scholar
  • 13 Lehmann JM, Kliewer SA, Moore LB, Smith-Oliver TA, Oliver BB, Su JL, Sundseth SS, Winegar DA, Blanchard DE, Spencer TA, Willson TM. Activation of the nuclear receptor LXR by oxysterols defines a new hormone response pathway. J Biol Chem 1997; 272: 3137-40.
    CrossrefPubMedGoogle Scholar
  • 14 Peet DJ, Turley SD, Ma W, Janowski BA, Lobaccaro JM, Hammer RE, Mangelsdorf DJ. Cholesterol and bile acid metabolism are impaired in mice lacking the nuclear oxysterol receptor LXR alpha. Cell 1998; 93: 693-704.
    CrossrefPubMedGoogle Scholar
  • 15 Repa JJ, Mangelsdorf DJ. The role of orphan nuclear receptors in the regulation of cholesterol homeostasis. Annu Rev Cell Dev Biol 2000; 16: 459-81.
    CrossrefPubMedGoogle Scholar
  • 16 Doolittle RF. Fibrinogen and fibrin. [Review. Annu Rev Biochem 1984; 53: 195-229.
    CrossrefPubMedGoogle Scholar
  • 17 Mosesson MW. Fibrin polymerization and its regulatory role in hemostasis. [Review. J Lab Clin Med 1990; 116: 8-17.
    PubMedGoogle Scholar
  • 18 Mosesson MW. The roles of fibrinogen and fibrin in hemostasis and thrombosis. [Review. Semin Hematol 1992; 29: 177-88.
    PubMedGoogle Scholar
  • 19 Blomback B. Fibrinogen and fibrin-proteins with complex roles in hemostasis and thrombosis. Thromb Res 1996; 83: 1-75.
    CrossrefPubMedGoogle Scholar
  • 20 Evans E, Courtois GM, Kilian PL, Fuller GM, Crabtree GR. Induction of fibrinogen and a subset of acute phase response genes involves a novel monokine which is mimicked by phorbol esters. J Biol Chem 1987; 262: 10850-4.
    PubMedGoogle Scholar
  • 21 Baumann H, Prowse KR, Marinkovic S, Won KA, Jahreis GP. Stimulation of hepatic acute phase response by cytokines and glucocorticoids. [Review. Ann N Y Acad Sci 1989; 557: 280-95.
    PubMedGoogle Scholar
  • 22 Grieninger G, Oddoux C, Diamond L, Weissbach L, Plant PW. Regulation of fibrino-gen synthesis and secretion by the chicken hepatocyte. Ann N Y Acad Sci 1989; 557: 257-70.
    PubMedGoogle Scholar
  • 23 Huber P, Laurent M, Dalmon J. Human beta-fibrinogen gene expression. Upstream sequences involved in its tissue specific expression and its dexamethasone and interleukin 6 stimulation. J Biol Chem 1990; 265: 5695-701.
    PubMedGoogle Scholar
  • 24 Hu CH, Harris JE, Davie EW, Chung DW. Characterization of the 5’-flanking region of the gene for the alpha chain of human fibrino-gen. J Biol Chem 1995; 270: 28342-9.
    CrossrefPubMedGoogle Scholar
  • 25 Mizuguchi J, Hu CH, Cao Z, Loeb KR, Chung DW, Davie EW. Characterization of the 5’-flanking region of the gene for the gamma chain of human fibrinogen. J Biol Chem 1995; 270: 28350-6.
    CrossrefPubMedGoogle Scholar
  • 26 Fuller GM, Zhang Z. Transcriptional control mechanism of fibrinogen gene expression. Ann N Y Acad Sci 2001; 936: 469-79.
    PubMedGoogle Scholar
  • 27 Kockx M, Princen HM, Kooistra T. Fibrate-modulated expression of fibrinogen, plasminogen activator inhibitor-1 and apolipoprotein A-l in cultured cynomolgus monkey hepatocytes – Role of the peroxisome proliferator-activated receptor-α. Thromb Haemost 1998; 80: 942-8.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 28 Binsack R, Stegmeier K, Dörge L, Völkl A. Bezafibrate down-regulates fibrinogen biosyn-thesis in human hepatoma HepG2 cells. Eur J Clin Invest 1998; 28: 151-63.
    CrossrefPubMedGoogle Scholar
  • 29 Kockx M, Gervois PP, Poulain P, Derudas B, Peters JM, Gonzalez FJ, Princen HM, Kooistra T, Staels B. Fibrates suppress fibrino-gen gene expression in rodents via activation of the peroxisome proliferator-activated receptor-alpha. Blood 1999; 93: 2991-8.
    PubMedGoogle Scholar
  • 30 Gervois P, Vu-Dac N, Kleemann R. et al. Negative regulation of human fibrinogen gene expression by peroxisome proliferator-activated receptor alpha agonists via inhibition of CCAAT box/enhancer-binding protein beta. J Biol Chem 2001; 276: 33471-7.
    CrossrefPubMedGoogle Scholar
  • 31 Kersten S, Desvergne B, Wahli W. Roles of PPARs in health and disease. Nature 2000; 405: 421-4.
    CrossrefPubMedGoogle Scholar
  • 32 Pineda TI, Gervois P, Staels B. Peroxisome proliferator-activated receptor alpha in metabolic disease, inflammation, atherosclerosis and aging. Curr Opin Lipidol 1999; 10: 151-9.
    CrossrefPubMedGoogle Scholar
  • 33 Nicodeme E, Nicaud M, Issandou M. Retinoids stimulate fibrinogen production both in vitro (hepatocytes) and in vivo. Induction requires activation of the retinoid X receptor. Arterioscler Thromb Vasc Biol 1995; 15: 1660-7.
    CrossrefPubMedGoogle Scholar
  • 34 Magana MM, Osborne TF. Two tandem binding sites for sterol regulatory element binding proteins are required for sterol regulation of fatty-acid synthase promoter. J Biol Chem 1996; 271: 32689-94.
    CrossrefPubMedGoogle Scholar
  • 35 Xia H, Redman C. The Degradation of Nascent Fibrinogen Chains Is Mediated by the Ubiquitin Proteasome Pathway. Biochem Biophys Res Commun 1999; 261: 590-7.
    CrossrefPubMedGoogle Scholar
  • 36 Xia H, Redman CM. Differential degradation of the three fibrinogen chains by proteasomes: involvement of Sec61p and cytosolic Hsp70. Arch Biochem Biophys 2001; 390: 137-45.
    CrossrefPubMedGoogle Scholar
  • 37 Roy SN, Mukhopadhyay G, Redman CM. Regulation of fibrinogen assembly. Transfection of Hep G2 cells with B beta cDNA specifically enhances synthesis of the three component chains of fibrinogen. J Biol Chem 1990; 265: 6389-93.
    PubMedGoogle Scholar
  • 38 Pai JT, Guryev O, Brown MS, Goldstein JL. Differential stimulation of cholesterol and unsaturated fatty acid biosynthesis in cells expressing individual nuclear sterol regulatory element-binding proteins. J Biol Chem 1998; 273: 26138-48.
    CrossrefPubMedGoogle Scholar
  • 39 Schultz JR, Tu H, Luk A. et al. Role of LXRs in control of lipogenesis. Genes Dev 2000; 14: 2831-8.
    CrossrefPubMedGoogle Scholar
  • 40 Repa JJ, Liang G, Ou J. et al. Regulation of mouse sterol regulatory element-binding protein-1c gene (SREBP-1c) by oxysterol receptors, LXRalpha and LXRbeta. Genes Dev 2000; 14: 2819-30.
    CrossrefPubMedGoogle Scholar
  • 41 Repa JJ, Turley SD, Lobaccaro JA. et al. Regulation of absorption and ABC1-mediated efflux of cholesterol by RXR heterodimers. Science 2000; 289: 1524-9.
    CrossrefPubMedGoogle Scholar
  • 42 Yoshikawa T, Shimano H, Amemiya-Kudo M. et al. Identification of liver X receptor-retinoid X receptor as an activator of the sterol regulatory element-binding protein 1c gene promoter. Mol Cell Biol 2001; 21: 2991-3000.
    CrossrefPubMedGoogle Scholar
  • 43 Chawla A, Repa JJ, Evans RM, Mangelsdorf DJ. Nuclear receptors and lipid physiology: opening the X-files. Science 2001; 294: 1866-70.
    CrossrefPubMedGoogle Scholar
  • 44 Rezaee F, Maas A, de Maat MP, Verheijen JH, Koopman J. Effect of genetic background and diet on plasma fibrinogen in mice. Possible relation with susceptibility to atherosclerosis. Atherosclerosis 2002; 164: 37-44.
    CrossrefPubMedGoogle Scholar