@article{10.1172/jci.insight.129556, author = {Charikleia Kalliora AND Ioannis D. Kyriazis AND Shin-ichi Oka AND Melissa J. Lieu AND Yujia Yue AND Estela Area-Gomez AND Christine J. Pol AND Ying Tian AND Wataru Mizushima AND Adave Chin AND Diego Scerbo AND P. Christian Schulze AND Mete Civelek AND Junichi Sadoshima AND Muniswamy Madesh AND Ira J. Goldberg AND Konstantinos Drosatos}, journal = {JCI Insight}, publisher = {The American Society for Clinical Investigation}, title = {Dual PPARα/γ activation inhibits SIRT1-PGC1α axis and causes cardiac dysfunction}, year = {2019}, month = {9}, volume = {4}, url = {https://insight.jci.org/articles/view/129556}, 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.}, number = {17}, doi = {10.1172/jci.insight.129556}, url = {https://doi.org/10.1172/jci.insight.129556}, }