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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 4

PPARα impairs PPARγ-mediated activation of PPARGC1A promoter activity.

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PPARα impairs PPARγ-mediated activation of PPARGC1A promoter activity.
(...
(A) PPARA, PPARG, and PPARGC1A mRNA levels were assessed in AC16 cells infected with recombinant adenoviruses (Ad) expressing PPARα or PPARγ (n = 6–12; data were collected from 2 independent experiments). *P < 0.05; ****P < 0.0001 vs. Ad-GFP; #P < 0.05; ####P < 0.0001 vs. Ad-PPARα; $$$$P < 0.0001 vs. Ad-PPARγ. (B) Ppargc1a mRNA levels in AC16 cells treated with 50 μM rosiglitazone (PPARγ agonist), 50 μM WY-14643 (PPARα agonist), a combination of rosiglitazone and WY-14643, or a combination of rosiglitazone, WY-14643, and 10 μM MK886 (PPARα antagonist) (B; n = 10–22; data were collected from 2 independent experiments). (C–F) Luciferase activity (fold change) in AC16 cells transfected with reporter plasmids containing the following human PPARγ coactivator 1-α (PPARGC1A) promoter fragments: pGL3-basic vector(BV)-PPARGC1A-1631 (C), pGL3BV-a-PPARGC1A-1386 (D), pGL3BV-a-PPARGC1A-1012 (E), pGL3BV-a-PPARGC1A-210 (F), followed by treatment with 50 μM rosiglitazone, 50 μM WY-14643, or a combination of both (n = 4–12). (B–F) Data were collected from 1 experiment. *P < 0.05; **P < 0.01; ***P < 0.001 vs. ctrl; #P < 0.05; ##P < 0.01 vs. rosiglitazone; $$P < 0.01 vs. WY-14642. (G) PPARα and PPARγ enrichment of the Ppargc1a gene promoter following chromatin immunoprecipitation from cardiac tissue obtained from C57BL/6 mice (n = 4). **P < 0.01. Statistical analyses were performed with 1-way ANOVA followed by Tukey’s post hoc correction. Error bars represent SEM.

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