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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 7

Resveratrol restores mitochondrial function, abundance, and lipid homeostasis in mice treated with tesaglitazar.

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Resveratrol restores mitochondrial function, abundance, and lipid homeos...
(A and B) Adult cardiomyocytes (ACMs) were obtained from C57BL/6 mice that were subjected to i.p. daily injections of tesaglitazar (TESA; 2 mg/kg bw) or a combination of tesaglitazar (2 mg/kg bw) and resveratrol (RSV) (100 mg/kg bw) for 7 days. Representative fluorescence microscopy images (A; original magnification, ×20; scale bar: 100 μm) of isolated ACMs stained with MitoTracker Red and quantitation (B) of mitochondrial number/total area (number of analyzed cells, 158 cells from 6 control [CTRL] mice; 157 cells from 6 tesaglitazar-fed mice; 157 cells from 3 mice treated with tesaglitazar and resveratrol [TESA+RSV]). All treatments were performed in 1 experiment. (C) Cardiac mitochondrial DNA (mtDNA) to nuclear DNA (nuDNA) ratio (fold change) in C57BL/6 mice fed with chow diet containing tesaglitazar (0.5 μmol/kg bw) or a combination of tesaglitazar (0.5 μmol/kg bw) and resveratrol (100 mg/kg bw/day) for 6 weeks, (n = 4–5). (D) Heatmap and correlation clustering following lipidomic analysis of hearts obtained from C57BL/6 mice fed with chow diet containing tesaglitazar or a combination of tesaglitazar and resveratrol for 6 weeks (n = 4). Statistical analyses were performed with 1-way ANOVA followed by Tukey’s post hoc correction among groups. ***P < 0.001 vs. chow. Error bars represent SEM.

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