Atherosclerosis
Volume 198, Issue 1 , Pages 198-207 , May 2008

Effects of ezetimibe and/or simvastatin on LDL receptor protein expression and on LDL receptor and HMG-CoA reductase gene expression: A randomized trial in healthy men

  • Ioanna Gouni-Berthold

      Affiliations

    • Department of Internal Medicine II, University of Cologne, Kerpener Street 62, 50937 Cologne, Germany
    • Corresponding Author InformationCorresponding author. Tel.: +49 221 478 4070; fax: +49 221 478 4179.
    • ,
  • Heiner K. Berthold

      Affiliations

    • Medical Faculty, Clinical Pharmacology, University of Bonn, Bonn, Germany
    • ,
  • Helena Gylling

      Affiliations

    • Department of Clinical Nutrition, University of Kuopio and Kuopio University Hospital, Kuopio, Finland
    • ,
  • Maarit Hallikainen

      Affiliations

    • Department of Clinical Nutrition, University of Kuopio and Kuopio University Hospital, Kuopio, Finland
    • ,
  • Eleni Giannakidou

      Affiliations

    • Department of Internal Medicine II, University of Cologne, Kerpener Street 62, 50937 Cologne, Germany
    • ,
  • Sebastian Stier

      Affiliations

    • Medical Policlinic, University of Bonn, Bonn, Germany
    • ,
  • Yon Ko

      Affiliations

    • Medical Policlinic, University of Bonn, Bonn, Germany
    • ,
  • Dilip Patel

      Affiliations

    • MRC Clinical Sciences Centre, Hammersmith Hospital, London, United Kingdom
    • ,
  • Anne K. Soutar

      Affiliations

    • MRC Clinical Sciences Centre, Hammersmith Hospital, London, United Kingdom
    • ,
  • Udo Seedorf

      Affiliations

    • Leibniz Institute for Arteriosclerosis Research, University of Münster, Münster, Germany
    • ,
  • Christos S. Mantzoros

      Affiliations

    • Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
    • ,
  • Jogchum Plat

      Affiliations

    • Department of Human Biology, Maastricht University, Maastricht, The Netherlands
    • ,
  • Wilhelm Krone

      Affiliations

    • Department of Internal Medicine II, University of Cologne, Kerpener Street 62, 50937 Cologne, Germany

Received 7 July 2007 ,Revised 22 September 2007 ,Accepted 24 September 2007.

References 

  1. Clader JW. The discovery of ezetimibe: a view from outside the receptor. J Med Chem. 2004;47:1–9
  2. Dujovne CA, Ettinger MP, McNeer JF, et al. Efficacy and safety of a potent new selective cholesterol absorption inhibitor, ezetimibe, in patients with primary hypercholesterolemia. Am J Cardiol. 2002;90:1092–1097
  3. Feldman T, Koren M, Insull W, et al. Treatment of high-risk patients with ezetimibe plus simvastatin co-administration versus simvastatin alone to attain national cholesterol education program adult treatment panel III low-density lipoprotein cholesterol goals. Am J Cardiol. 2004;93:1481–1486
  4. Kong W-J, Liu J, Jiang J-D. Human low-density lipoprotein receptor gene and its regulation. J Mol Med. 2006;84:29–36
  5. Attie AD, Seidah NG. Dual regulation of the LDL receptor-some clarity and new questions. Cell Metab. 2005;1:290–292
  6. Brown MS, Goldstein JL. The SREBP pathway: regulation of cholesterol metabolism by proteolysis of a membrane-bound transcription factor. Cell. 1997;89:331–340
  7. Engelking LJ, Liang G, Hammer RE, et al. Schonheimer effect explained-feedback regulation of cholesterol synthesis in mice mediated by Insig proteins. J Clin Invest. 2005;115:2489–2498
  8. Goldstein JL, Brown MS. Regulation of the mevalonate pathway. Nature. 1990;343:425–430
  9. Conde K, Roy S, Freake H, Newton RS, Fernandez ML. Atorvastatin and simvastatin have distinct effects on hydroxy methylglutaryl-CoA reductase activity and mRNA abundance in the guinea pig. Lipids. 1999;34:1327–1332
  10. Sudhop T, Lutjohann D, Kodal A, et al. Inhibition of intestinal cholesterol absorption by ezetimibe in humans. Circulation. 2002;106:1943–1948
  11. Powell EE, Kroon PA. Low density lipoprotein receptor and 3-hydroxy-3-methylglutaryl coenzyme A reductase gene expression in human mononuclear leukocytes is regulated coordinately and parallels gene expression in human liver. J Clin Invest. 1994;93:2168–2174
  12. Aggarwahl D, Freake H, Soliman GA, Dutta A, Fernandez M-L. Validation of using gene expression in mononuclear cells as a marker for hepatic cholesterol metabolism. Lipids Health Dis. 2006;5:22–25
  13. Björkhem I, Miettinen T, Reihner E, et al. Correlation between serum levels of some cholesterol precursors and activity of HMG-CoA reductase in human liver. J Lipid Res. 1987;28:1137–1143
  14. Miettinen TA, Tilvis RS, Kesaniemi YA. Serum plant sterols and cholesterol precursors reflect cholesterol absorption and synthesis in volunteers of a randomly selected male population. Am J Epidemiol. 1990;131:20–31
  15. Miettinen TA. Cholesterol metabolism during ketoconazole treatment in man. J Lipid Res. 1988;29:43–51
  16. De AK, Roach SE, De M, et al. Development of a simple method for rapid isolation of polymorphonuclear leukocytes from human blood. J Immunoassay Immunochem. 2005;26:35–42
  17. Chomczynski P. A reagent for single-step simulataneous isolation of RNA, DNA and proteins from cell and tissue samples. Biotechniques. 1993;15:532–536
  18. Chomczynski P, Mackey K. Short technical reports: modification of the TRI reagent procedure for isolation of RNA from polysaccharide- and proteoglycan-rich sources. Biotechniques. 1995;19:942–945
  19. Fronhoffs S. A method for the rapid construction of cRNA standard curves in quantitative real-time reverse transcription polymerase chain reaction. Mol Cell Probes. 2002;16:99–110
  20. Totzke G, Sachinidis A, Vetter H, Ko Y. Competitive reverse transcription/polymerase chain reaction for the quantification of p53 and mdm2 mRNA expression. Mol Cell Probes. 1996;10:427–433
  21. Seedorf U, Engel T, Lueken A, et al. Cholesterol absorption inhibitor ezetimibe blocks uptake of oxidized LDL in human macrophages. Biochem Biophys Res Commun. 2004;320:1337–1341
  22. Plat J, Mensink RP. Effects of plant stanol esters on LDL receptor protein expression and on LDL receptor and HMG-CoA reductase mRNA expression in mononuclear blood cells of healthy men and women. FASEB J. 2002;16:258–260
  23. Jialal I, Kappagoda T. Therapy and clinical trials: ezetimibe. Curr Opin Lipidol. 2003;14:643–646
  24. Miettinen T, Gylling H. Effect of statins on noncholesterol sterol levels. Implications for use of plant stanols and sterols. Am J Cardiol. 2005;96:40D–46D
  25. Miettinen TA, Strandberg TE, Gylling H. Noncholesterol sterols and cholesterol lowering by long-term simvastatin treatment in coronary patients. Arterioscler Thromb Vasc Biol. 2000;20:1340–1346
  26. Hidaka H, Kojima H, Kawabata T, et al. Effects of an HMG-CoA reductase inhibitor, pravastatin, and bile sequestering resin, cholestyramine, on plasma plant sterol levels in hypercholesterolemic subjects. J Atheroscler Thromb. 1995;2:60–65
  27. Sudhop T, von Bergmann K. Cholesterol absorption inhibitors for the treatment of hypercholestrolemia. Drugs. 2002;62:2333–2347
  28. Ness GC, Chambers CM. Feedback and hormonal regulation of hepatic 3-hydroxy-3-methylglutaryl coenzyme A reductase: the concept of cholesterol buffering capacity. Proc Soc Exp Biol Med. 2000;224:8–19
  29. Ness GC, Holland RC, Lopez D. Selective compensatory induction of hepatic HMG-CoA reductase in response to inhibition of cholesterol absorption. Exp Biol Med. 2006;231:559–565
  30. Rudling M, Angelin B, Stähle L, et al. Regulation of hepatic low-density lipoprotein receptor, 3-hydroxy-3-methylglutaryl coenzyme A reductase, and cholesterol 7a-hydroxylase mRNAs in human liver. J Clin Endocrinol Metab. 2002;87:4307–4313
  31. Valasek MA, Weng J, Shaul PW, Anderson RGW, Repa JJ. Caveolin-1 is not required for murine intestinal cholesterol transport. J Biol Chem. 2005;280:28103–28109
  32. Gagne C, Gaudet D, Bruckert E. Efficacy and safety of ezetimibe coadministered with atorvastatin or simvastatin in patients with homozygous familial hypercholesterolemia. Circulation. 2002;105:2469–2475
  33. Repa JJ, Turley SD, Quan G, Dietschy JM. Delienation of molecular changes in intrahepatic cholesterol metabolism resulting from diminished cholesterol absorption. J Lipid Res. 2005;46:779–789
  34. Tremblay AJ, Lamarche B, Cohn JJ, et al. Effects of ezetimibe on the in vivo kinetics of apoB-48 and apoB-100 in men with primary hypercholesterolemia. Arterioscler Thromb Vasc Biol. 2006;26:1101–1106
  35. Ness GC, Zhao Z, Lopez D. Inhibitors of cholesterol biosynthesis increase hepatic low density lipoprotein receptor protein degradation. Arch Biochem Biophys. 1996;325:242–248
  36. Dubuc G, Chamberland A, Wassef H, et al. Statins up-regulate PCSK9, the gene encoding the proprotein convertase neural apoptosis-regulated convertase-1 implicated in familial hypercholesterolemia. Arterioscler Thromb Vasc Biol. 2004;8:1454–1459
  37. Field FJ, Watt K, Mathur SN. Ezetimibe interferes with cholesterol trafficking from the plasma membrane to the endoplasmic reticulum in Caco-2 cells. J Lipid Res. 2007;48:1735–1745
  38. Telford DE, Sutherland BG, Edwards JY, et al. The molecular mechanisms underlying the reduction of LDL apoB100 by ezetimibe plus simvastatin. J Lipid Res. 2007;48:699–708
  39. During A, Dawson HD, Harrison EH. Carotenoid transport is decreased and expression of the lipid transporters SR-BI, NPC1L1, and ABCA1 is down-regulated in Caco-2 cells treated with ezetimibe. J Nutr. 2005;135:2305–2312
  40. Lally S, Tan CY, Owens D, Tomkin GH. Messenger RNA levels of genes involved in dysregulation of postprandial lipoproteins in type 2 diabetes: the role of Niemann-Pick C1-like 1, ATP-binding cassette, transporters G5 and G8, and of microsomal triglyceride transfer protein. Diabetologia. 2006;49:1008–1016

PII: S0021-9150(07)00597-7

doi: 10.1016/j.atherosclerosis.2007.09.034

Atherosclerosis
Volume 198, Issue 1 , Pages 198-207 , May 2008

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