Identification of ERRalpha as a specific partner of PGC-1alpha for the activation of PDK4 gene expression in muscle

The FEBS Journal
Makoto Araki, Kiyoto Motojima

Abstract

Pyruvate dehydrogenase kinase 4 (PDK4) is a key regulatory enzyme involved in switching the energy source from glucose to fatty acids in response to physiological conditions. Transcription of the PDK4 gene is activated by fasting or by the administration of a PPARalpha ligand in a tissue-specific manner. Here, we show that the two mechanisms are independent, and that ERRalpha is directly involved in PPARalpha-independent transcriptional activation of the PDK4 gene with PGC-1alpha as a specific partner. This conclusion is based on the following evidence. First, detailed mutation analyses of the cloned PDK4 gene promoter sequence identified a possible ERRalpha-binding motif as the PGC-1alpha responsive element. Second, overexpression of ERRalpha by cotransfection enhanced, and the knockout of it by shRNAs diminished, PGC-1alpha-dependent activation. Third, specific binding of ERRalpha to the identified PGC-1alpha responsive sequence was confirmed by the electrophoresis mobility shift assay. Finally, cell-type-specific responsiveness to PGC-1alpha was observed and this could be explained by differences in the expression levels of ERRalpha, however, ectopic expression of ERRalpha in poorly responsive cells did not restore PGC-1alph...Continue Reading

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Citations

May 30, 2008·Proceedings of the National Academy of Sciences of the United States of America·Ada AoJianrong Lu
Apr 30, 2008·Human Molecular Genetics·Guillermo MariñoCarlos López-Otín
Mar 21, 2012·Molecular and Cellular Biology·Sushama KamarajugaddaJianrong Lu
Jun 12, 2012·Nutrition & Metabolism·Rita Rinnankoski-TuikkaHeikki Kainulainen
Jan 5, 2007·Yakugaku zasshi : Journal of the Pharmaceutical Society of Japan·Makoto ArakiKiyoto Motojima
Feb 28, 2013·International Journal of Molecular Sciences·Zhengtang QiShuzhe Ding
Feb 14, 2014·Nutrition & Metabolism·Shuai ZhangElizabeth R Gilbert
Jul 5, 2007·Proceedings of the National Academy of Sciences of the United States of America·Sibylle JägerBruce M Spiegelman
Aug 26, 2009·Molecular and Cellular Endocrinology·Sara ConnaughtonEdwards A Park
Sep 10, 2008·Trends in Endocrinology and Metabolism : TEM·Josep A Villena, Anastasia Kralli
Jan 1, 2007·Obesity Research & Clinical Practice·A J McAinchD Cameron-Smith
Dec 6, 2012·Journal of Bone and Mineral Research : the Official Journal of the American Society for Bone and Mineral Research·Edith Bonnelye, Jane E Aubin
Sep 7, 2014·Molecular Biology Reports·Abena Nsiah-SefaaVictoria C Foletta
Aug 26, 2014·The Biochemical Journal·Minako ImamuraLawrence Chan
Jan 5, 2008·Nuclear Receptor Signaling·Annie M Tremblay, Vincent Giguère
Nov 7, 2012·Diabetes & Metabolism Journal·Ji Yun JeongIn-Kyu Lee
Nov 3, 2006·The Journal of Biological Chemistry·Yi ZhangEdwards A Park
Jan 3, 2018·The Journal of Clinical Endocrinology and Metabolism·Shintaro YamaguchiJun Yoshino
Apr 27, 2019·Frontiers in Endocrinology·Hui XiaVincent Giguère
Jan 12, 2011·Journal of Medicinal Chemistry·Raymond J PatchMicheal D Gaul

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