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


K. Motojima, Department of Biochemistry, Meiji Pharmaceutical University, 2-522-1 Noshio, Kiyose, Tokyo 204-8588, Japan
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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 PPARα ligand in a tissue-specific manner. Here, we show that the two mechanisms are independent, and that ERRα is directly involved in PPARα-independent transcriptional activation of the PDK4 gene with PGC-1α 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 ERRα-binding motif as the PGC-1α responsive element. Second, overexpression of ERRα by cotransfection enhanced, and the knockout of it by shRNAs diminished, PGC-1α-dependent activation. Third, specific binding of ERRα to the identified PGC-1α responsive sequence was confirmed by the electrophoresis mobility shift assay. Finally, cell-type-specific responsiveness to PGC-1α was observed and this could be explained by differences in the expression levels of ERRα, however, ectopic expression of ERRα in poorly responsive cells did not restore PGC-1α responsiveness, indicating that ERRα is necessary, but not sufficient for the response.