Liver-specific peroxisome proliferator-activated receptor alpha target gene regulation by the angiotensin type 1 receptor blocker telmisartan.
OBJECTIVE
The angiotensin type 1 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 PPARalpha pathway. RESEARCH DESIGN AND METHODS; Regulation of PPARalpha 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 PPARalpha ligand binding domain (LBD) was investigated using transactivation assays.


RESULTS
Telmisartan significantly induced the PPARalpha 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 PPARalpha. Telmisartan consistently activated the PPARalpha-LBD as a partial PPARalpha agonist. Despite high in vitro concentrations required for PPARalpha activation, telmisartan (3 mg x kg(-1) x 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 PPARalpha target gene induction may be the result of previously reported high hepatic concentrations of telmisartan.


CONCLUSIONS
The present study identifies the ARB/PPARgamma modulator telmisartan as a partial PPARalpha agonist. As a result of its particular pharmacokinetic profile, PPARalpha activation by telmisartan seems to be restricted to the liver. Hepatic PPARalpha activation may provide an explanation for telmisartan's antidyslipidemic actions observed in recent clinical trials.
Clemenz
Markus
M
Center for Cardiovascular Research, Institute of Pharmacology, Charité-Universitätsmedizin Berlin, Hessische Str. 3-4, 10115 Berlin, Germany.
Frost
Nikolaj
N
Schupp
Michael
M
Caron
Sandrine
S
Foryst-Ludwig
Anna
A
Böhm
Christian
C
Hartge
Martin
M
Gust
Ronald
R
Staels
Bart
B
Unger
Thomas
T
Kintscher
Ulrich
U
D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology*; D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology*; D001565:Benzoates / Q000494:pharmacology*; D002460:Cell Line; D045744:Cell Line, Tumor; D005786:Gene Expression Regulation / Q000187:drug effects*; D020868:Gene Silencing; D017930:Genes, Reporter; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000502:physiology*; D008113:Liver Neoplasms; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D047493:PPAR alpha / Q000235:genetics*; D016133:Polymerase Chain Reaction; D034741:RNA, Small Interfering / Q000235:genetics; D000077333:Telmisartan; D015533:Transcriptional Activation; D014162:Transfection
D047228:Angiotensin II Type 1 Receptor Blockers; D001562:Benzimidazoles; D001565:Benzoates; D047493:PPAR alpha; D034741:RNA, Small Interfering; D000077333:Telmisartan