PGC-1alpha coactivates PDK4 gene expression via the orphan nuclear receptor ERRalpha: a mechanism for transcriptional control of muscle glucose metabolism.

Academic Article

Abstract

  • The transcriptional coactivator PGC-1alpha 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-1alpha expression in skeletal muscle coordinately upregulate the expression of pyruvate dehydrogenase kinase 4 (PDK4), a negative regulator of glucose oxidation. Forced expression of PGC-1alpha in C(2)C(12) myotubes induced PDK4 mRNA and protein expression. PGC-1alpha-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-1alpha-responsive element bound the estrogen-related receptor alpha (ERRalpha), a recently identified component of the PGC-1alpha signaling pathway. In addition, PGC-1alpha was shown to activate ERRalpha expression. Chromatin immunoprecipitation assays confirmed that PGC-1alpha and ERRalpha occupied the mPDK4 promoter in C(2)C(12) myotubes. Additionally, transfection studies using ERRalpha-null primary fibroblasts demonstrated that ERRalpha is required for PGC-1alpha-mediated activation of the mPDK4 promoter. As predicted by the effects of PGC-1alpha on PDK4 gene transcription, overexpression of PGC-1alpha in C(2)C(12) myotubes decreased glucose oxidation rates. These results identify the PDK4 gene as a new PGC-1alpha/ERRalpha target and suggest a mechanism whereby PGC-1alpha exerts reciprocal inhibitory influences on glucose catabolism while increasing alternate mitochondrial oxidative pathways in skeletal muscle.
  • Authors

    Published In

    Keywords

  • Animals, Base Sequence, Binding Sites, Gene Expression, Gene Expression Regulation, Enzymologic, Glucose, Male, Mice, Mice, Inbred C57BL, Molecular Sequence Data, Muscle Fibers, Skeletal, Muscle, Skeletal, Oxidation-Reduction, PPAR alpha, Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha, Promoter Regions, Genetic, Protein Kinases, Receptors, Cytoplasmic and Nuclear, Receptors, Estrogen, Response Elements, Trans-Activators, Transcription Factors, Up-Regulation
  • Digital Object Identifier (doi)

    Pubmed Id

  • 22190195
  • Authorlist

  • Wende AR; Huss JM; Schaeffer PJ; Giguère V; Kelly DP
  • Start Page

  • 10684
  • End Page

  • 10694
  • Volume

  • 25
  • Issue

  • 24