Liver-specific peroxisome proliferator-activated receptor α target gene regulation by the angiotensin type 1 receptor blocker telmisartan

OBJECTIVE-The angiotensin type I receptor blocker (ARB) and peroxisome proliferator-activated receptor (PPAR) gamma 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 PPARot pathway. RESEARCH DESIGN AND METHODS-Regulation of PPAR alpha 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 PPARa ligand binding domain (LBD) was investigated using transactivation assays. RESULTS-Telmisartan significantly induced the PPAR alpha target genes carnitine palmitoyl transferase 1A (CPT1A) in human HepG2 cells and acyl-CoA synthetase long-chain family member I (ACSL1) in murine AML12 cells in the micromolar range. Telmisartan-induced CPT1A stimulation was markedly reduced after small interfering RNA-mediated knockdown of PPAR alpha. Telmisartan consistently activated the PPAR alpha-LBD as a partial PPAR alpha agonist. Despite high in vitro concentrations required for PPAR alpha activation, telmisartan (3 mg center dot kg(-1)center dot day(-1)) potently increased ACSL1 and CPT1A expression in liver from diet-induced obese mice associated with a marked decrease of hepatic and serum tliglycerides. Muscular CPT1B expression was not affected. Tissue specificity of telmisartan-induced PPAR alpha target gene induction may be the result of previously reported high hepatic concentrations of telmisartan. CONCLUSIONS-The present study identifies the ARB/PPAR gamma modulator telmisartan as a partial PPARa agonist. As a result of its particular pharmacokinetic profile, PPAR alpha activation by telmisartan seems to be restricted to the liver. Hepatic PPAR alpha activation may provide an explanation for telmisartan's antidyslipidemic actions observed in recent clinical trials.