PGC-1α Coactivates PDK4 Gene Expression via the Orphan Nuclear Receptor ERRα: a Mechanism for Transcriptional Control of Muscle Glucose Metabolism
- 1 December 2005
- journal article
- research article
- Published by Taylor & Francis Ltd in Molecular and Cellular Biology
- Vol. 25 (24), 10684-10694
- https://doi.org/10.1128/mcb.25.24.10684-10694.2005
Abstract
The transcriptional coactivator PGC-1α 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-1α expression in skeletal muscle coordinately upregulate the expression of pyruvate dehydrogenase kinase 4 (PDK4), a negative regulator of glucose oxidation. Forced expression of PGC-1α in C2C12 myotubes induced PDK4 mRNA and protein expression. PGC-1α-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-1α-responsive element bound the estrogen-related receptor α (ERRα), a recently identified component of the PGC-1α signaling pathway. In addition, PGC-1α was shown to activate ERRα expression. Chromatin immunoprecipitation assays confirmed that PGC-1α and ERRα occupied the mPDK4 promoter in C2C12 myotubes. Additionally, transfection studies using ERRα-null primary fibroblasts demonstrated that ERRα is required for PGC-1α-mediated activation of the mPDK4 promoter. As predicted by the effects of PGC-1α on PDK4 gene transcription, overexpression of PGC-1α in C2C12 myotubes decreased glucose oxidation rates. These results identify the PDK4 gene as a new PGC-1α/ERRα target and suggest a mechanism whereby PGC-1α exerts reciprocal inhibitory influences on glucose catabolism while increasing alternate mitochondrial oxidative pathways in skeletal muscle.Keywords
This publication has 58 references indexed in Scilit:
- PGC-1α Deficiency Causes Multi-System Energy Metabolic Derangements: Muscle Dysfunction, Abnormal Weight Control and Hepatic SteatosisPLoS Biology, 2005
- A Polymorphic Autoregulatory Hormone Response Element in the Human Estrogen-related Receptor α (ERRα) Promoter Dictates Peroxisome Proliferator-activated Receptor γ Coactivator-1α Control of ERRα ExpressionOnline Journal of Public Health Informatics, 2004
- Reduced Fat Mass in Mice Lacking Orphan Nuclear Receptor Estrogen-Related Receptor αMolecular and Cellular Biology, 2003
- Overexpression of Peroxisome Proliferator-activated Receptor γ Coactivator-1α Down-regulates GLUT4 mRNA in Skeletal MusclesOnline Journal of Public Health Informatics, 2003
- PGC-1α-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetesNature Genetics, 2003
- Transcriptional co-activator PGC-1α drives the formation of slow-twitch muscle fibresNature, 2002
- Adaptive Increase in Pyruvate Dehydrogenase Kinase 4 during Starvation Is Mediated by Peroxisome Proliferator-Activated Receptor αBiochemical and Biophysical Research Communications, 2001
- In Skeletal Muscle, Glucose Storage and Oxidation Are Differentially Impaired by the IR1152 Mutant ReceptorOnline Journal of Public Health Informatics, 1997
- Nuclear Orphan Receptor as a Repressor of Glucocorticoid Receptor Transcriptional ActivityOnline Journal of Public Health Informatics, 1996
- THE GLUCOSE FATTY-ACID CYCLE ITS ROLE IN INSULIN SENSITIVITY AND THE METABOLIC DISTURBANCES OF DIABETES MELLITUSThe Lancet, 1963