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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 8

Resveratrol blocks the cardiotoxic effect of tesaglitazar in diabetic mice.

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Resveratrol blocks the cardiotoxic effect of tesaglitazar in diabetic mi...
Leptin receptor–deficient (db/db) mice were treated with regular chow or chow containing either tesaglitazar (TESA; 0.5 μmol/kg bw) or a combination of tesaglitazar (0.5 μmol/kg bw) and resveratrol (RSV) (100 mg/kg bw/day) for 6 weeks. Plasma triglycerides (TG) (A) and plasma glucose (B) were determined throughout the treatment. Representative short-axis M-mode images (C), left ventricular fractional shortening (D), and mitochondrial DNA (mtDNA) to nuclear DNA (nuDNA) ratio (fold change) (E) were determined upon termination of the treatment (n = 4; data were collected from 1 experiment). Cardiac acetylated–PPARγ coactivator 1-α (Ac-PGC1α) normalized to IgG heavy chain, and total PGC1α, sirtuin 1 (SIRT1), and β-ACTIN immunoblots (F) and densitometric analysis (G and H) of db/db mice fed on regular chow, tesaglitazar-containing chow, or chow that contains tesaglitazar and resveratrol diet for 6 weeks (n = 4; data were collected from 1 experiment). Statistical analysis was performed with 1-way ANOVA followed by Tukey’s post hoc correction. *P < 0.05; **P < 0.01 vs. chow; #P < 0.05 vs. tesaglitazar. Error bars represent SEM.

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