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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 9

Cardiac SIRT1 ablation abrogates resveratrol beneficial effects in tesaglitazar-mediated cardiac dysfunction.

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Cardiac SIRT1 ablation abrogates resveratrol beneficial effects in tesag...
(A–H) C57BL/6 mice fed high-fat diet (HFD) or HFD containing tesaglitazar (0.5 μmol/kg bw) for 6 weeks (data were collected from 1 experiment). Upon completion of the treatment, plasma triglycerides (TG; A) and glucose levels (B) were determined. Representative short-axis M-mode images (C) and left ventricular fractional shortening (D) of C57BL/6 mice fed regular or tesaglitazar-containing HFD for 6 weeks (n = 5–6). Cardiac PPARγ coactivator 1-α (Ppargc1a) (E; n = 4–5) gene expression, acetylated PPARγ coactivator 1-α (Ac-PGC1α; n = 6) normalized to IgG heavy chain, and total PGC1α (n = 8), sirtuin 1 (SIRT1; n = 8), and β-ACTIN immunoblots (F) and their densitometric analysis (G–I) from C57BL/6 mice treated with regular or tesaglitazar-containing HFD (0.5 μmol/kg bw). (J and K) Representative short-axis M-mode images (J) and left ventricular fractional shortening (%) (K) of C57BL/6 mice and α myosin heavy chain–Sirt1–/– (aMHC-Sirt1–/–) mice fed regular chow or chow containing a combination of tesaglitazar (0.5 μmol/kg bw) and resveratrol (RSV; 100 mg/kg bw/d) (n = 5–8; data were collected from 2 independent experiments). Statistical analysis for A–I was performed with unpaired 2-tailed Student’s t tests. Statistical analysis for K was performed with 1-way ANOVA followed by Tukey’s post hoc correction. *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001 vs. HFD (A–I) or chow C57BL6 (K). ###P < 0.001 vs. tesaglitazar plus RSV C57BL/6. $$P < 0.01 vs. chow aMHC-Sirt1–/–. Error bars represent SEM. (L) Schematic representation of the proposed model. Tesaglitazar treats hyperlipidemia and hyperglycemia but suppresses SIRT1 and PGC1α, which reduces mitochondrial abundance and causes cardiac dysfunction. The aggravating effect of tesaglitazar on cardiac function is alleviated by coadministration of RSV.

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