HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text (PDF) Online-Only Appendix All Versions of this Article: db07-0839v1 57/5/1405    most recent Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Clemenz, M. Articles by Kintscher, U. Search for Related Content PubMed PubMed Citation Articles by Clemenz, M. Articles by Kintscher, U. Social Bookmarking                What's this?

Liver-Specific PPAR-Target Gene Regulation by the Angiotensin Type 1 Receptor Blocker Telmisartan

¹Center for Cardiovascular Research (CCR), Institute of Pharmacology, Charité-Universitätsmedizin Berlin, Germany
²Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, University of Pennsylvania, School of Medicine, Philadelphia, Pennsylvania, USA
³UR 545 INSERM, Institute Pasteur de Lille, Université de Lille 2, Lille, France
⁴Institute of Pharmacy, Free University of Berlin, Germany

Objective: The angiotensin type 1 receptor blocker (ARB) and PPAR-modulator telmisartan has been recently demonstrated to reduce plasma triglycerides in non-diabetic 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 (DIO). 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 µ-molar range. Telmisartan-induced CPT1A stimulation was markedly reduced after siRNA-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 (3mg/kg/d) potently increased ACSL1 and CPT1A expression in liver from DIO-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 anti-dyslipidemic actions observed in recent clinical trials.

CiteULike    Del.icio.us    Digg    Reddit    Technorati    What's this?