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

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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4 Scopus citations

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 tesaglitazarcontaining 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.

Original languageEnglish (US)
Article numbere129556
JournalJCI Insight
Volume4
Issue number17
DOIs
StatePublished - Sep 5 2019
Externally publishedYes

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ASJC Scopus subject areas

  • Medicine(all)

Cite this

Kalliora, C., Kyriazis, I. D., Oka, S. I., Lieu, M. J., Yue, Y., Area-Gomez, E., Pol, C. J., Tian, Y., Mizushima, W., Chin, A., Scerbo, D., Schulze, P. C., Civelek, M., Sadoshima, J., Madesh, M., Goldberg, I. J., & Drosatos, K. (2019). Dual PPARα/γ activation inhibits SIRT1-PGC1α axis and causes cardiac dysfunction. JCI Insight, 4(17), [e129556]. https://doi.org/10.1172/jci.insight.129556