Hsieh, M. C., Das, D., Sambandam, N., Zhang, M. Q., Nahle, Z. (October 2008) Regulation of the PDK4 isozyme by the Rb-E2F1 complex. J Biol Chem, 283 (41). pp. 27410-7.
Abstract
Loss of the transcription factor E2F1 elicits a complex metabolic phenotype in mice underscored by reduced adiposity and protection from high fat diet-induced diabetes. Here, we demonstrate that E2F1 directly regulates the gene encoding PDK4 (pyruvate dehydrogenase kinase 4), a key nutrient sensor and modulator of glucose homeostasis that is chronically elevated in obesity and diabetes and acutely induced under the metabolic stress of starvation or fasting. We show that loss of E2F1 in vivo blunts PDK4 expression and improves myocardial glucose oxidation. The absence of E2F1 also corresponds to lower blood glucose levels, improved plasma lipid profile, and increased sensitivity to insulin stimulation. Consistently, enforced E2F1 expression up-regulates PDK4 levels and suppresses glucose oxidation in C(2)C(12) myoblasts. Furthermore, inactivation of Rb, the repressor of E2F-dependent transcription, markedly induces PDK4 and triggers the enrichment of E2F1 occupancy onto the PDK4 promoter as detected by chromatin immunoprecipitation analysis. Two overlapping E2F binding sites were identified on this promoter. Transactivation assays later verified E2F1 responsiveness of this promoter element in C(2)C(12) myoblasts and IMR90 fibroblasts, an effect that was completely abrogated following mutation of the E2F sites. Taken together, our data illustrate how the E2F1 mitogen directly regulates PDK4 levels and influences cellular bioenergetics, namely mitochondrial glucose oxidation. These results are relevant to the pathophysiology of chronic diseases like obesity and diabetes, where PDK4 is dysregulated and could have implications pertinent to the etiology of tumor metabolism, especially in cancers with Rb pathway defects.
| Item Type: | Paper |
|---|---|
| Subjects: | diseases & disorders bioinformatics > genomics and proteomics > genetics & nucleic acid processing bioinformatics > genomics and proteomics diseases & disorders > nutritional and metabolic diseases bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification diseases & disorders > nutritional and metabolic diseases > diabetes bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > transcription factor |
| CSHL Authors: | |
| Communities: | CSHL labs > Zhang lab |
| Depositing User: | Matt Covey |
| Date: | 10 October 2008 |
| Date Deposited: | 25 Feb 2013 20:58 |
| Last Modified: | 25 Feb 2013 20:58 |
| Related URLs: | |
| URI: | https://repository.cshl.edu/id/eprint/27609 |
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