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Liver-Specific Peroxisome Proliferator–Activated Receptor Target Gene

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Liver-Specific Peroxisome Proliferator–Activated Receptor Target Gene ORIGINAL ARTICLE Liver-Specific Peroxisome Proliferator–Activated Receptor ␣ Target Gene Regulation by the Angiotensin Type 1 Receptor Blocker Telmisartan Markus Clemenz,1 Nikolaj Frost,1 Michael Schupp,2 Sandrine Caron,3 Anna Foryst-Ludwig,1 Christian Bo¨hm,1 Martin Hartge,1 Ronald Gust,4 Bart Staels,4 Thomas Unger,1 and Ulrich Kintscher1 ␣ OBJECTIVE—The angiotensin type 1 receptor blocker (ARB) PPAR target gene induction may be the result of previously and peroxisome proliferator–activated receptor (PPAR) ␥ mod- reported high hepatic concentrations of telmisartan. ulator telmisartan has been recently demonstrated to reduce CONCLUSIONS—The present study identifies the ARB/PPAR␥ plasma triglycerides in nondiabetic and diabetic hypertensive modulator telmisartan as a partial PPAR␣ agonist. As a result of patients. The present study investigates the molecular mecha- its particular pharmacokinetic profile, PPAR␣ activation by telm- nisms of telmisartans hypolipidemic actions, in particular its ␣ ␣ isartan seems to be restricted to the liver. Hepatic PPAR effect on the PPAR pathway. activation may provide an explanation for telmisartan’s antidys- RESEARCH DESIGN AND METHODS—Regulation of PPAR␣ lipidemic actions observed in recent clinical trials. Diabetes 57: target genes by telmisartan was studied by real-time PCR and 1405–1413, 2008 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. ngiotensin type 1 receptor blockers (ARBs) are RESULTS—Telmisartan significantly induced the PPAR␣ target commonly used in the treatment of hyperten- genes carnitine palmitoyl transferase 1A (CPT1A) in human sion and related cardiovascular and organ dam- HepG2 cells and acyl-CoA synthetase long-chain family member age (1). Recently, a distinct subgroup of ARBs 1 (ACSL1) in murine AML12 cells in the micromolar range. A has been identified as partial agonists for the peroxisome Telmisartan-induced CPT1A stimulation was markedly reduced ␥ ␣ proliferator–activated receptor (PPAR) with selective after small interfering RNA–mediated knockdown of PPAR . PPAR␥ modulating properties (2–4). In contrast to full Telmisartan consistently activated the PPAR␣-LBD as a partial ␥ PPAR␣ agonist. Despite high in vitro concentrations required for glitazone agonists, PPAR -activating ARBs exert selective PPAR␣ activation, telmisartan (3 mg ⅐ kgϪ1 ⅐ dayϪ1) potently recruitment of nuclear cofactors resulting in in vivo insulin increased ACSL1 and CPT1A expression in liver from diet- sensitization in the absence of weight gain in obese induced obese mice associated with a marked decrease of insulin-resistant mice (3). Among the ARBs, telmisartan hepatic and serum triglycerides. Muscular CPT1B expression has been shown to be the most potent PPAR␥ modulator was not affected. Tissue specificity of telmisartan-induced (3,4). Based on these in vitro results and data from animal experiments, a number of clinical studies (5–9) have been conducted in which the metabolic actions of the PPAR␥- From the 1Center for Cardiovascular Research, Institute of Pharmacology, activating ARB telmisartan have been intensively investi- Charite´-Universita¨tsmedizin Berlin, Berlin, Germany; the 2Division of Endo- crinology, Diabetes, and Metabolism, Department of Medicine, University of gated. When compared with ARBs that do not exert Pennsylvania, School of Medicine, Philadelphia, Pennsylvania; the 3Unite´de PPAR␥-activating properties, telmisartan not only im- Recherche 545 Institut National de la Sante´ et de la Recherche Me´dicale, proves insulin sensitivity but also induces beneficial ac- Institute Pasteur de Lille, Universite´ de Lille 2, Lille, France; and the 4Institute tions on serum lipid levels such as a reduction of serum of Pharmacy, Free University of Berlin, Berlin, Germany. Corresponding author: Prof. Ulrich Kintscher, MD, Center for Cardiovascu- triglycerides. (5,10,11) lar Research, Institute of Pharmacology, Charite´-Universita¨tsmedizin Berlin, PPARs are ligand-activated transcription factors belong- Hessische Str. 3-4, 10115 Berlin, Germany. E-mail: ulrich.kintscher@ ing to the superfamily of nuclear receptors. PPAR␥ is charite.de. Received for publication 20 June 2007 and accepted in revised form 2 abundantly expressed in adipose tissue and a major regu- January 2008. lator of insulin and glucose metabolism (12). In contrast, Published ahead of print at http://diabetes.diabetesjournals.org on 9 Janu- PPAR␣ is highly expressed in tissues displaying a high ary 2008. DOI: 10.2337/db07-0839. Additional information for this article can be found in an online appendix at metabolic rate of fatty acids, such as the liver and skeletal http://dx.doi.org/10.2337/db07-0839. muscle (13). PPAR␣ modulates intracellular lipid metabo- M.C. and N.F. contributed equally to this article. lism by transcriptional regulation of genes involved in fatty T.U. is a member of the speakers bureau of and has received grant/research support from Boehringer Ingelheim and Bayer Schering Pharma. U.K. is a acid uptake, mitochondrial fatty acid oxidation, and tri- member of the speakers bureau of Bayer Schering Pharma and has received glyceride catabolism (13,14). Natural PPAR␣ ligands com- grant/research support from Boehringer Ingelheim and Bayer Schering prise mono- and polyunsaturated fatty acids as well as Pharma. ␣ ACSL1, acyl-CoA synthetase long-chain family member 1; ALT, alanine eicosanoids (15). In addition, PPAR is also the molecular aminotransferase; ARB, angiotensin type 1 receptor blocker; AST, aspartate target of lipid-lowering fibrates such as gemfibrozil, beza- aminotransferase; CPT1A, carnitine palmitoyl transferase 1A; hPPAR␣, human fibrate, clofibrate, and fenofibrate. These substances are peroxisome proliferator–activated receptor ␣; LBD, ligand binding domain; used to treat dyslipidemia and cardiovascular disease. NASH, nonalcoholic steatohepatitis; PPAR, peroxisome proliferator–activated receptor; siRNA, small interfering RNA. (13,15) © 2008 by the American Diabetes Association. It has been reported that certain PPAR␥ activators such The costs of publication of this article were defrayed in part by the payment of page ␣ charges. This article must therefore be hereby marked “advertisement” in accordance as pioglitazone are also able to activate PPAR . Further- with 18 U.S.C. Section 1734 solely to indicate this fact. more, it has been proposed that the positive actions of DIABETES, VOL. 57, MAY 2008 1405 TELMISARTAN AND PPAR␣ pioglitazone on diabetic dyslipidemia might at least in part for 16 weeks, followed by randomization to either a vehicle-treated (n ϭ 6) (0.5% Tween 80/H O), a telmisartan-treated (n ϭ 6) (3 mg ⅐ kgϪ1 ⅐ dayϪ1), or be mediated by its PPAR␣-activating abilities (16,17). To 2 a pioglitazone-treated (n ϭ 6) (10 mg ⅐ kgϪ1 ⅐ dayϪ1) group. Telmisartan was understand the underlying mechanism of telmisartan’s provided by Boehringer Ingelheim, and piogliatzone was extracted from lipid-lowering actions we studied the effect of telmisartan tablets. Animals were treated by oral gavage for 10 weeks. Before and after on major PPAR␣ target genes involved in fatty acid treatment, blood samples were collected from overnight-fasted animals by oxidation in the human hepatoma cell line HepG2, the retroorbital venous puncture under isoflurane anesthesia for analysis of serum murine hepatic cell line AML12, and in liver/skeletal mus- triglycerides (enzymatic-colorimetric test; Cypress Diagnostics). After the exper- cle of diet-induced obese mice treated with telmisartan. iment, animals were killed and organs were dissected. All animal procedures Furthermore, activation of the PPAR␣ ligand binding were in accordance with institutional guidelines and were approved. ␣ Triglyceride content in liver was measured as described previously (19). domain (LBD) and regulation of PPAR protein/mRNA Briefly, tissues were homogenized in liquid nitrogen and treated with ice-cold expression by telmisartan was studied. chloroform/methanol/water mixture (2:1:0.8) for 2 min. After centrifugation, The present study demonstrates that telmisartan in- the aqueous layer was removed and the chloroform layer was decanted. The duces the PPAR␣ target gene carnitine palmitoyl trans- mixture was incubated at 70°C for chloroform clearance, and the residues ferase 1 (CPT1A) in HepG2 cells and acyl-CoA synthetase were dissolved in isopropanol and assessed for the triglyceride content using long-chain family member 1 (ACSL1) in AML12 cells. an enzymatic-colorimetric test (Cypress Diagnostics), according to the man- ␣ ufacturer’s instructions. For immunohistochemical studies, organs were fixed Consistently, telmisartan acts as a partial PPAR agonist in 4% formalin, embedded in paraffin, and stained with hematoxylin/eosin. in PPAR␣ transactivation assays and induces PPAR␣ Statistical analysis. ANOVA, followed by multiple comparison testing or t expression. High-fat diet–fed mice treated with telmisar- test, was performed for statistical analysis as appropriate. Statistical signifi- tan showed a pronounced induction of hepatic ACSL1 and cance was designated at P Ͻ 0.05. Values are expressed as means Ϯ SE or as CPT1A, which was associated with a significant decrease indicated. of hepatic and serum triglycerides. Interestingly, CPT1B expression in skeletal muscle was not affected by telmis- RESULTS artan. Tissue specificity of telmisartan-induced PPAR␣ Telmisartan induces PPAR␣ target gene expression
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