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Dual PPARα/γ activation inhibits SIRT1-PGC1α axis and causes cardiac dysfunction
Charikleia Kalliora, … , Ira J. Goldberg, Konstantinos Drosatos
Charikleia Kalliora, … , Ira J. Goldberg, Konstantinos Drosatos
Published August 8, 2019
Citation Information: JCI Insight. 2019;4(17):e129556. https://doi.org/10.1172/jci.insight.129556.
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Research Article Metabolism

Dual PPARα/γ activation inhibits SIRT1-PGC1α axis and causes cardiac dysfunction

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Abstract

Dual PPARα/γ agonists that were developed to target hyperlipidemia and hyperglycemia in patients with type 2 diabetes caused cardiac dysfunction or other adverse effects. We studied the mechanisms that underlie the cardiotoxic effects of a dual PPARα/γ agonist, tesaglitazar, in wild-type and diabetic (leptin receptor–deficient, db/db) mice. Mice treated with tesaglitazar-containing chow or high-fat diet developed cardiac dysfunction despite lower plasma triglycerides and glucose levels. Expression of cardiac PPARγ coactivator 1-α (PGC1α), which promotes mitochondrial biogenesis, had the most profound reduction among various fatty acid metabolism genes. Furthermore, we observed increased acetylation of PGC1α, which suggests PGC1α inhibition and lowered sirtuin 1 (SIRT1) expression. This change was associated with lower mitochondrial abundance. Combined pharmacological activation of PPARα and PPARγ in C57BL/6 mice reproduced the reduction of PGC1α expression and mitochondrial abundance. Resveratrol-mediated SIRT1 activation attenuated tesaglitazar-induced cardiac dysfunction and corrected myocardial mitochondrial respiration in C57BL/6 and diabetic mice but not in cardiomyocyte-specific Sirt1–/– mice. Our data show that drugs that activate both PPARα and PPARγ lead to cardiac dysfunction associated with PGC1α suppression and lower mitochondrial abundance, likely due to competition between these 2 transcription factors.

Authors

Charikleia Kalliora, Ioannis D. Kyriazis, Shin-ichi Oka, Melissa J. Lieu, Yujia Yue, Estela Area-Gomez, Christine J. Pol, Ying Tian, Wataru Mizushima, Adave Chin, Diego Scerbo, P. Christian Schulze, Mete Civelek, Junichi Sadoshima, Muniswamy Madesh, Ira J. Goldberg, Konstantinos Drosatos

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Figure 2

PPARα interferes with PPARγ-mediated induction of tesaglitazar on Ppargc1a expression.

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PPARα interferes with PPARγ-mediated induction of tesaglitazar on Ppargc...
(A) C57BL/6 mice injected i.p. with 25, 12.5, 6.25, and 3.125 mg/kg of body weight (bw) rosiglitazone (PPARγ agonist) and 3.125 mg/kg bw WY-14643 (PPARα agonist) or a combination of rosiglitazone (25 mg/kg bw) and WY-14643 (12.5 mg/kg bw) to assess the cardiac PPARγ coactivator 1-α (Ppargc1a) mRNA levels (n = 6–16). Control (CTRL) mice (n = 26) received DMSO. (B and C) C57BL/6 mice were treated i.p. with rosiglitazone (25 mg/kg bw), WY-14643 (12.5 mg/kg bw), or a combination of rosiglitazone (25 mg/kg body weight) and WY-14643 (12.5 mg/kg bw) and cardiac cluster of differentiation (Cd36), lipoprotein lipase (Lpl), and angiopoietin like-4 (Angptl4) (B; n = 4–8) and carnitine palmitoyltransferase 1-β (Cpt1b), acyl-CoA oxidase 1 (Acox1), medium-chain acyl-CoA dehydrogenase (Acadm), long-chain acyl-CoA dehydrogenase (Acadl), very-long-chain acyl-CoA dehydrogenase (Acadvl), uncoupling protein 2 (Ucp2), and Ucp3 (C; n = 4–10) mRNA levels were assessed. Control mice were treated with DMSO. Statistical analyses were performed with 1-way ANOVA followed by Tukey’s correction. Error bars represent SEM. *P < 0.05 vs. CTRL; **P < 0.01 vs CTRL. #P < 0.05 vs. rosiglitasone (25 mg/kg bw); ##P < 0.01 vs. rosiglitasone (25 mg/kg bw). $P < 0.05 vs. WY-14643 (25 mg/kg bw); $$P < 0.05 vs. WY-14643 (25 mg/kg bw). The data presented here were collected from 2–3 independent experiments.

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