Liver-Specific Peroxisome Proliferator–Activated Receptor α Target Gene Regulation by the Angiotensin Type 1 Receptor Blocker Telmisartan

  1. Markus Clemenz1,
  2. Nikolaj Frost1,
  3. Michael Schupp2,
  4. Sandrine Caron3,
  5. Anna Foryst-Ludwig1,
  6. Christian Böhm1,
  7. Martin Hartge1,
  8. Ronald Gust4,
  9. Bart Staels4,
  10. Thomas Unger1 and
  11. Ulrich Kintscher1
  1. 1Center for Cardiovascular Research, Institute of Pharmacology, Charité-Universitätsmedizin Berlin, Berlin, Germany
  2. 2Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, University of Pennsylvania, School of Medicine, Philadelphia, Pennsylvania
  3. 3Unité de Recherche 545 Institut National de la Santé et de la Recherche Médicale, Institute Pasteur de Lille, Université de Lille 2, Lille, France
  4. 4Institute of Pharmacy, Free University of Berlin, Berlin, Germany
  1. Corresponding author: Prof. Ulrich Kintscher, MD, Center for Cardiovascular Research, Institute of Pharmacology, Charité-Universitätsmedizin Berlin, Hessische Str. 3-4, 10115 Berlin, Germany. E-mail: ulrich.kintscher{at}charite.de

Abstract

OBJECTIVE—The angiotensin type 1 receptor blocker (ARB) and peroxisome proliferator–activated receptor (PPAR) γ modulator telmisartan has been recently demonstrated to reduce plasma triglycerides in nondiabetic and diabetic hypertensive patients. The present study investigates the molecular mechanisms of telmisartans hypolipidemic actions, in particular its effect on the PPARα pathway.

RESEARCH DESIGN AND METHODS—Regulation of PPARα target genes by telmisartan was studied by real-time PCR and Western immunoblotting in vitro and in vivo in liver/skeletal muscle of mice with diet-induced obesity. Activation of the PPARα ligand binding domain (LBD) was investigated using transactivation assays.

RESULTS—Telmisartan significantly induced the PPARα target genes carnitine palmitoyl transferase 1A (CPT1A) in human HepG2 cells and acyl-CoA synthetase long-chain family member 1 (ACSL1) in murine AML12 cells in the micromolar range. Telmisartan-induced CPT1A stimulation was markedly reduced after small interfering RNA–mediated knockdown of PPARα. Telmisartan consistently activated the PPARα-LBD as a partial PPARα agonist. Despite high in vitro concentrations required for PPARα activation, telmisartan (3 mg · kg−1 · day−1) potently increased ACSL1 and CPT1A expression in liver from diet-induced obese mice associated with a marked decrease of hepatic and serum triglycerides. Muscular CPT1B expression was not affected. Tissue specificity of telmisartan-induced PPARα target gene induction may be the result of previously reported high hepatic concentrations of telmisartan.

CONCLUSIONS—The present study identifies the ARB/PPARγ modulator telmisartan as a partial PPARα agonist. As a result of its particular pharmacokinetic profile, PPARα activation by telmisartan seems to be restricted to the liver. Hepatic PPARα activation may provide an explanation for telmisartan's antidyslipidemic actions observed in recent clinical trials.

Footnotes

  • Published ahead of print at http://diabetes.diabetesjournals.org on 9 January 2008. DOI: 10.2337/db07-0839.

  • Additional information for this article can be found in an online appendix at http://dx.doi.org/10.2337/db07-0839.

  • M.C. and N.F. contributed equally to this article.

  • T.U. is a member of the speakers bureau of and has received grant/research support from Boehringer Ingelheim and Bayer Schering Pharma. U.K. is a member of the speakers bureau of Bayer Schering Pharma and has received grant/research support from Boehringer Ingelheim and Bayer Schering Pharma.

  • The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

    • Accepted January 2, 2008.
    • Received June 20, 2007.
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  1. Diabetes vol. 57 no. 5 1405-1413
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