Liver-Specific Peroxisome Proliferator–Activated Receptor α Target Gene Regulation by the Angiotensin Type 1 Receptor Blocker Telmisartan

Abstract

OBJECTIVE-The angiotensin type 1 receptor blocker (ARB) and peroxisome proliferator-activated receptor (PPAR) ␥ 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 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. 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 micromolar range. Telmisartan-induced CPT1A stimulation was markedly reduced after small interfering RNA-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 (3 mg ⅐ kg Ϫ1 ⅐ day Ϫ1 ) potently increased ACSL1 and CPT1A expression in liver from dietinduced obese 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 antidyslipidemic actions observed in recent clinical trials.

Angiotensin II type 1 receptor-independent beneficial effects of telmisartan on dietary-induced obesity, insulin resistance and fatty liver in mice

“…Consistent with previous reports [4,5], we have demonstrated that telmisartan treatment (3 mg/kg) did not affect food intake (Electronic supplementary material [ESM] Fig. 1b), but substantially attenuated HFD-induced obesity (ESM Fig.…”

“…Recently, it was shown to be a partial agonist of the peroxisome proliferatoractivated receptor (PPAR)γ in cultured cells [3,4] and to activate PPARα in cultured hepatic cells and in liver of wild-type mice fed a high-fat diet (HFD) [5]. Telmisartan has also been reported to improve HFD-induced obesity, insulin resistance and fatty liver in wild-type animals [4,5]. However, the extent to which AT1 inhibition contributes to the beneficial effects of telmisartan treatment has not yet been established.…”

Impact of RGS2 deficiency on the therapeutic effect of telmisartan in angiotensin II-induced aortic aneurysm

“…Recent studies have shown that telmisartan improves the metabolism of lipids and glucose. 22,23 Our study showed that low-density lipoprotein-cholesterol levels were significantly decreased in the AngII+Telmi group compared with the Figure 1 Blood pressure changes in response to AngII or AngII plus telmisartan. Systolic blood pressure (SBP) variations were shown in Rgs2 +/+ , Rgs2 +/À and Rgs2 À/À mice.…”

“…Moreover, some reports have characterized new functions of telmisartan as a partial agonist for peroxisome proliferator-activated receptors (PPARs). 22,23,27 Activation of PPARa by agonists or telmisartan induces an anti-inflammatory response through the repression of nuclear factor-kB signaling in umbilical vein endothelial cells and aortic smooth muscle cells in vitro 27,28 and inhibits macrophage infiltration and reduces aortic dilatation in a mouse model of aortic aneurysm. 29 PPARa and PPARg improve lipid and glucose metabolism, respectively.…”

Analysis of copy number variation in 8,842 Korean individuals reveals 39 genes associated with hepatic biomarkers AST and ALT

“…An AST/ALT ratio of less than one implies moderate liver disease, such as nonalcoholic fatty liver disease (NAFLD). In contrast, an AST/ALT ratio greater than one implies severe liver disease, such as chronic hepatitis or alcoholic fatty liver disease (7). Two loci (10q24.2 and 22 q13.31) have been identified as influencing the plasma levels of ALT in three European populations (Switzerland: n = 5,636, Italy: n = 1,200, London: n = 879) (8).…”