TY - JOUR AU - Kalliora, Charikleia AU - Kyriazis, Ioannis D. AU - Oka, Shin-ichi AU - Lieu, Melissa J. AU - Yue, Yujia AU - Area-Gomez, Estela AU - Pol, Christine J. AU - Tian, Ying AU - Mizushima, Wataru AU - Chin, Adave AU - Scerbo, Diego AU - Schulze, P. Christian AU - Civelek, Mete AU - Sadoshima, Junichi AU - Madesh, Muniswamy AU - Goldberg, Ira J. AU - Drosatos, Konstantinos T1 - Dual PPARα/γ activation inhibits SIRT1-PGC1α axis and causes cardiac dysfunction PY - 2019/09/05/ AB - 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. JF - JCI Insight JA - JCI Insight SN - 2379-3708 DO - 10.1172/jci.insight.129556 VL - 4 IS - 17 UR - https://doi.org/10.1172/jci.insight.129556 PB - The American Society for Clinical Investigation ER -