期刊
MOLECULAR AND CELLULAR BIOLOGY
卷 25, 期 24, 页码 10684-10694出版社
AMER SOC MICROBIOLOGY
DOI: 10.1128/MCB.25.24.10684-10694.2005
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资金
- NHLBI NIH HHS [T32 HL007275] Funding Source: Medline
- NIDDK NIH HHS [P30 DK52574, R01 DK045416, P30 DK052574, P30 DK056341, P30 DK56341, R01 DK45416] Funding Source: Medline
The transcriptional coactivator PGC-1 alpha is a key regulator of energy metabolism, yet little is known about its role in control of substrate selection. We found that physiological stimuli known to induce PGC-1 alpha expression in skeletal muscle coordinately upregulate the expression of pyruvate dehydrogenase kinase 4 (PDK4), a negative regulator of glucose oxidation. Forced expression of PGC-1 alpha in C2C12 myotubes induced PDK4 mRNA and protein expression. PGC-1 alpha-mediated activation of PDK4 expression was shown to occur at the transcriptional level and was mapped to a putative nuclear receptor binding site. Gel shift assays demonstrated that the PGC-1 alpha-responsive element bound the estrogen-related receptor alpha (ERR alpha), a recently identified component of the PGC-1 alpha signaling pathway. In addition, PGC-1 alpha was shown to activate ERR alpha expression. Chromatin immunoprecipitation assays confirmed that PGC-1 alpha and ERR alpha occupied the mPDK4 promoter in C2C12 myotubes. Additionally, transfection studies using ERR alpha-null primary fibroblasts demonstrated that ERR alpha is required for PGC-1 alpha-mediated activation of the mPDK4 promoter. As predicted by the effects of PGC-1 alpha on PDK4 gene transcription, overexpression of PGC-1 alpha in C2C12 myotubes decreased glucose oxidation rates. These results identify the PDK4 gene as a new PGC-1/ERR alpha target and suggest a mechanism whereby PGC-1 alpha exerts reciprocal inhibitory influences on glucose catabolism while increasing alternate mitochondrial oxidative pathways in skeletal muscle.
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