エネルギー代謝調節鍵酵素PDK4の正常時及び病態時における発現調節(誌上シンポジウム)  [in Japanese] Transcriptional Regulation of Metabolic Switching PDK4 Gene under Various Physiological Conditions(Symposium Review)  [in Japanese]

Pyruvate dehydrogenase kinase 4 (PDK4) phosphorylates and inactivates the pyruvate dehydrogenase complex to respond to physiologic conditions. This response switches the energy source from glucose to fatty acids to maintain blood glucose levels. Transcription of the PDK4 gene is activated by fasting or by the administration of a peroxisome proliferator-activated receptor α (PPARα) ligand in a tissue-specific manner. However, the two mechanisms to induce PDK4 mRNA as well as the relationship between the two have not been studied in detail. In this study, we show that the two mechanisms are independent, at least in the mouse skeletal muscle, and that estrogen-related receptor α (ERRα) is directly involved in the PPARα-independent transcriptional activation of the PDK4 gene with peroxisome proliferator-activated receptor γ co-activator 1α (PGC-1α) as a specific partner. The latter conclusion is based on the following evidence: 1) Deletion and point mutation analyses of the cloned mouse PDK4 gene promoter sequence identified an exact possible ERRα-binding motif as the PGC-1α responsive element. 2) The overexpression of ERRα by cotransfection enhanced, and the knocking down of it by specific shRNAs diminished, the PGC-1α-dependent activation. 3) Specific binding of ERRα to the identified PGC-1α-responsive sequence of the mouse PDK4 promoter was confirmed in the electrophoresis mobility shift assay using anti-ERRα antibodies. These results suggest that PGC-1α plays an essential role not only in regulating the amounts of energy creating enzymes, but also at the step of metabolic switching with unevenly distributed tissue transcription factors such as ERRα in the skeletal muscle, thus harmonizing tissue-specific functions and energy metabolism.