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

¹ Center for Cardiovascular Research, Institute of Pharmacology, Charité-Universitätsmedizin Berlin, Berlin, Germany
² Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, University of Pennsylvania, School of Medicine, Philadelphia, Pennsylvania
³ Unité de Recherche 545 Institut National de la Santé et de la Recherche Médicale, Institute Pasteur de Lille, Université de Lille 2, Lille, France
⁴ Institute of Pharmacy, Free University of Berlin, Berlin, Germany

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

Key Words: ACSL1, acyl-CoA synthetase long-chain family member 1 • ALT, alanine aminotransferase • ARB, angiotensin type 1 receptor blocker • AST, aspartate aminotransferase • CPT1A, carnitine palmitoyl transferase 1A • hPPAR, human peroxisome proliferator–activated receptor • LBD, ligand binding domain; NASH, nonalcoholic steatohepatitis • PPAR, peroxisome proliferator–activated receptor • siRNA, small interfering RNA

OBJECTIVE—The angiotensin type 1 receptor blocker (ARB) and peroxisome proliferator–activated receptor (PPAR) 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 PPAR pathway.

RESEARCH DESIGN AND METHODS—Regulation of PPAR 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 PPAR ligand binding domain (LBD) was investigated using transactivation assays.

RESULTS—Telmisartan significantly induced the PPAR 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 PPAR. Telmisartan consistently activated the PPAR-LBD as a partial PPAR agonist. Despite high in vitro concentrations required for PPAR 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 PPAR target gene induction may be the result of previously reported high hepatic concentrations of telmisartan.

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

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