Dua PPARα/γ activation inhibits SIRT1-PGC1α axis and causes cardiac dysfunction

Dual PPAR alpha/gamma 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 PPAR alpha/gamma 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 PPAR gamma coactivator 1-alpha (PGC1 alpha), which promotes mitochondrial biogenesis. had the most profound reduction among various fatty acid metabolism genes. Furthermore, we observed increased acetylation of PGC1 alpha, which suggests PGC1 alpha inhibition and lowered sirtuin 1 (SIRT1) expression. This change was associated with lower mitochondrial abundance. Combined pharmacological activation of PPAR alpha. and PPAR gamma in C57BL/6 mice reproduced the reduction of PGC1 alpha 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 PPAR alpha and PPAR gamma lead to cardiac dysfunction associated with PGC1 alpha suppression and lower mitochondrial abundance, likely due to competition between these 2 transcription factors.