Separation of the gluconeogenic and mitochondrial functions of PGC-1α through S6 kinase
- Yaniv Lustig1,
- Jorge L. Ruas1,
- Jennifer L. Estall1,
- James C. Lo1,
- Srikripa Devarakonda1,
- Dina Laznik1,
- Jang Hyun Choi1,
- Hiraku Ono2,
- Jesper V. Olsen3 and
- Bruce M. Spiegelman1,4
- 1Department of Cell Biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA;
- 2Department of Internal Medicine, Division of Endo/Diabetes, Saitama Medical University, Saitama 350-0495, Japan;
- 3Department of Proteomics, Novo Nordisk Foundation Center for Protein Research, Faculty of Health Sciences, University of Copenhagen, Copenhagen DK-2200, Denmark
Abstract
PGC-1α is a transcriptional coactivator that powerfully regulates many pathways linked to energy homeostasis. Specifically, PGC-1α controls mitochondrial biogenesis in most tissues but also initiates important tissue-specific functions, including fiber type switching in skeletal muscle and gluconeogenesis and fatty acid oxidation in the liver. We show here that S6 kinase, activated in the liver upon feeding, can phosphorylate PGC-1α directly on two sites within its arginine/serine-rich (RS) domain. This phosphorylation significantly attenuates the ability of PGC-1α to turn on genes of gluconeogenesis in cultured hepatocytes and in vivo, while leaving the functions of PGC-1α as an activator of mitochondrial and fatty acid oxidation genes completely intact. These phosphorylations interfere with the ability of PGC-1α to bind to HNF4α, a transcription factor required for gluconeogenesis, while leaving undisturbed the interactions of PGC-1α with ERRα and PPARα, factors important for mitochondrial biogenesis and fatty acid oxidation. These data illustrate that S6 kinase can modify PGC-1α and thus allow molecular dissection of its functions, providing metabolic flexibility needed for dietary adaptation.
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Footnotes
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↵4 Corresponding author.
E-MAIL bruce_spiegelman{at}dfci.harvard.edu.
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Article published online ahead of print. Article and publication date are online at http://www.genesdev.org/cgi/doi/10.1101/gad.2054711.
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Supplemental material is available for this article.
- Received March 29, 2011.
- Accepted May 10, 2011.
- Copyright © 2011 by Cold Spring Harbor Laboratory Press