Dual peroxisome-proliferator-activated-receptor-α/γ activation inhibits SIRT1-PGC1α axis and causes cardiac dysfunction

JCI Insight
Charikleia KallioraKonstantinos Drosatos

Abstract

Dual peroxisome proliferator-activated receptor (PPAR)α/γ agonists that were developed to target hyperlipidemia and hyperglycemia in type 2 diabetes patients, 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 peroxisome proliferator-activated receptor gamma coactivator 1-alpha (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 di...Continue Reading

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Citations

Dec 17, 2019·Acta Physiologica·Marina Makrecka-KukaTerje S Larsen
Jun 27, 2020·Journal of Cardiovascular Pharmacology and Therapeutics·John R Richards
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Nov 10, 2020·Journal of Cardiovascular Pharmacology·Charikleia Kalliora, Konstantinos Drosatos
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Methods Mentioned

BETA
immunoprecipitation
acetylation
transgenic
transfect
PCR

Software Mentioned

CLUSTAL O
Genomatix

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