{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T08:58:37Z","timestamp":1790758717121,"version":"4.1.0"},"reference-count":79,"publisher":"American Society for Clinical Investigation","issue":"17","funder":[{"DOI":"10.13039\/100000050","name":"National Heart Lung Blood Institute","doi-asserted-by":"crossref","award":["HL112853,HL130218,HL073029,HL135987"],"award-info":[{"award-number":["HL112853,HL130218,HL073029,HL135987"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100001340","name":"W. W. 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We studied the mechanisms that underlie the cardiotoxic effects of a dual PPAR\u03b1\/\u03b3 agonist, tesaglitazar, in wild-type and diabetic (leptin receptor\u2013deficient,\n                    <jats:italic>db\/db<\/jats:italic>\n                    ) 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\u03b3 coactivator 1-\u03b1 (PGC1\u03b1), which promotes mitochondrial biogenesis, had the most profound reduction among various fatty acid metabolism genes. Furthermore, we observed increased acetylation of PGC1\u03b1, which suggests PGC1\u03b1 inhibition and lowered sirtuin 1 (SIRT1) expression. This change was associated with lower mitochondrial abundance. Combined pharmacological activation of PPAR\u03b1 and PPAR\u03b3 in C57BL\/6 mice reproduced the reduction of PGC1\u03b1 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\n                    <jats:italic>\n                      Sirt1\n                      <jats:sup>\u2013\/\u2013<\/jats:sup>\n                    <\/jats:italic>\n                    mice. Our data show that drugs that activate both PPAR\u03b1 and PPAR\u03b3 lead to cardiac dysfunction associated with PGC1\u03b1 suppression and lower mitochondrial abundance, likely due to competition between these 2 transcription factors.\n                  <\/jats:p>","DOI":"10.1172\/jci.insight.129556","type":"journal-article","created":{"date-parts":[[2019,8,8]],"date-time":"2019-08-08T12:02:19Z","timestamp":1565265739000},"source":"Crossref","is-referenced-by-count":65,"title":["Dual PPAR\u03b1\/\u03b3 activation inhibits SIRT1-PGC1\u03b1 axis and causes cardiac dysfunction"],"prefix":"10.1172","volume":"4","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6686-7796","authenticated-orcid":true,"given":"Charikleia","family":"Kalliora","sequence":"first","affiliation":[{"name":"Center for Translational Medicine, Department of Pharmacology, Lewis Katz School of Medicine at Temple University, Philadelphia, Pennsylvania, USA."},{"name":"Faculty of Medicine, University of Crete, Voutes, Greece."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ioannis D.","family":"Kyriazis","sequence":"additional","affiliation":[{"name":"Center for Translational Medicine, Department of Pharmacology, Lewis Katz School of Medicine at Temple University, Philadelphia, Pennsylvania, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7481-9009","authenticated-orcid":true,"given":"Shin-ichi","family":"Oka","sequence":"additional","affiliation":[{"name":"Cardiovascular Research Institute, Department of Cell Biology and Molecular Medicine, Rutgers New Jersey Medical School, Newark, New Jersey, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melissa J.","family":"Lieu","sequence":"additional","affiliation":[{"name":"Center for Translational Medicine, Department of Pharmacology, Lewis Katz School of Medicine at Temple University, Philadelphia, Pennsylvania, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2893-4791","authenticated-orcid":true,"given":"Yujia","family":"Yue","sequence":"additional","affiliation":[{"name":"Center for Translational Medicine, Department of Pharmacology, Lewis Katz School of Medicine at Temple University, Philadelphia, Pennsylvania, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Estela","family":"Area-Gomez","sequence":"additional","affiliation":[{"name":"Department of Neurology, Columbia University Irving Medical Center, New York, New York, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christine J.","family":"Pol","sequence":"additional","affiliation":[{"name":"Center for Translational Medicine, Department of Pharmacology, Lewis Katz School of Medicine at Temple University, Philadelphia, Pennsylvania, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying","family":"Tian","sequence":"additional","affiliation":[{"name":"Center for Translational Medicine, Department of Pharmacology, Lewis Katz School of Medicine at Temple University, Philadelphia, Pennsylvania, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wataru","family":"Mizushima","sequence":"additional","affiliation":[{"name":"Cardiovascular Research Institute, Department of Cell Biology and Molecular Medicine, Rutgers New Jersey Medical School, Newark, New Jersey, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adave","family":"Chin","sequence":"additional","affiliation":[{"name":"Cardiovascular Research Institute, Department of Cell Biology and Molecular Medicine, Rutgers New Jersey Medical School, Newark, New Jersey, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diego","family":"Scerbo","sequence":"additional","affiliation":[{"name":"Division of Preventive Medicine and Nutrition, Columbia University, New York, New York, USA."},{"name":"NYU Langone School of Medicine, Division of Endocrinology, Diabetes and Metabolism, New York, New York, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9442-7141","authenticated-orcid":true,"given":"P. 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