Abstract

Objective: The angiotensin type 1 receptor blocker (ARB) and PPARγ-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 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 (DIO). 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 μ-molar range. Telmisartan-induced CPT1A stimulation was markedly reduced after siRNA-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 (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 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 anti-dyslipidemic actions observed in recent clinical trials.