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CREB controls hepatic lipid metabolism through nuclear hormone receptor PPAR-γ

Nature volume 426, pages 190–193 (2003)Cite this article

Abstract

Fasting triggers a series of hormonal cues that promote energy balance by inducing glucose output and lipid breakdown in the liver1. In response to pancreatic glucagon and adrenal cortisol, the cAMP-responsive transcription factor CREB activates gluconeogenic and fatty acid oxidation programmes by stimulating expression of the nuclear hormone receptor coactivator PGC-1 (refs 2–5). In parallel, fasting also suppresses lipid storage and synthesis (lipogenic) pathways1, but the underlying mechanism is unknown. Here we show that mice deficient in CREB activity have a fatty liver phenotype and display elevated expression of the nuclear hormone receptor PPAR-γ, a key regulator of lipogenic genes6,7. CREB inhibits hepatic PPAR-γ expression in the fasted state by stimulating the expression of the Hairy Enhancer of Split (HES-1) gene, a transcriptional repressor that is shown here to be a mediator of fasting lipid metabolism in vivo. The coordinate induction of PGC-1 and repression of PPAR-γ by CREB during fasting provides a molecular rationale for the antagonism between insulin and counter-regulatory hormones, and indicates a potential role for CREB antagonists as therapeutic agents in enhancing insulin sensitivity in the liver.

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Figure 1: Mice deficient in hepatic CREB activity display a fatty liver phenotype.
Figure 2: PPAR-γ mediates effects of CREB on triglyceride metabolism in liver.
Figure 3: HES-1 is a direct CREB target in vivo.
Figure 4: HES-1 mediates CREB-dependent inhibition of the lipogenic pathway during fasting.

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References

  1. Saltiel, A. R. New perspectives into the molecular pathogenesis and treatment of type 2 diabetes. Cell 104, 517–529 (2001)

    Article  CAS  Google Scholar 

  2. Herzig, S. et al. CREB regulates hepatic gluconeogenesis through the coactivator PGC-1. Nature 413, 179–183 (2001)

    Article  ADS  CAS  Google Scholar 

  3. Puigserver, P. et al. Insulin-regulated hepatic gluconeogenesis through FOXO1–PGC-1α interaction. Nature 423, 550–555 (2003)

    Article  ADS  CAS  Google Scholar 

  4. Vega, R. B., Huss, J. M. & Kelly, D. P. The coactivator PGC-1 cooperates with peroxisome proliferator-activated receptor α in transcriptional control of nuclear genes encoding mitochondrial fatty acid oxidation enzymes. Mol. Cell. Biol. 20, 1868–1876 (2000)

    Article  CAS  Google Scholar 

  5. Yoon, J. C. et al. Control of hepatic gluconeogenesis through the transcriptional coactivator PGC-1. Nature 413, 131–138 (2001)

    Article  ADS  CAS  Google Scholar 

  6. Yu, S. et al. Adipocyte-specific gene expression and adipogenic steatosis in the mouse liver due to peroxisome proliferator-activated receptor γ 1 (PPAR-γ1) overexpression. J. Biol. Chem. 278, 498–505 (2003)

    Article  CAS  Google Scholar 

  7. Matsusue, K. et al. Liver-specific disruption of PPARγ in leptin-deficient mice improves fatty liver but aggravates diabetic phenotypes. J. Clin. Invest. 111, 737–747 (2003)

    Article  CAS  Google Scholar 

  8. Rudolph, D. et al. Impaired fetal T cell development and perinatal lethality in mice lacking the cAMP response element binding protein. Proc. Natl Acad. Sci. USA 95, 4481–4486 (1998)

    Article  ADS  CAS  Google Scholar 

  9. Horton, J. D. & Shimomura, I. Sterol regulatory element-binding proteins: activators of cholesterol and fatty acid biosynthesis. Curr. Opin. Lipidol. 10, 143–150 (1999)

    Article  CAS  Google Scholar 

  10. Conkright, M. D. et al. Genome-wide analysis of CREB target genes reveals a core promoter requirement for cAMP responsiveness. Mol. Cell 11, 1101–1108 (2003)

    Article  CAS  Google Scholar 

  11. Fajas, L. et al. The organization, promoter analysis, and expression of the human PPAR-γ gene. J. Biol. Chem. 272, 18779–18789 (1997)

    Article  CAS  Google Scholar 

  12. Fajas, L. et al. Regulation of peroxisome proliferator-activated receptor γ expression by adipocyte differentiation and determination factor 1/sterol regulatory element binding protein 1: implications for adipocyte differentiation and metabolism. Mol. Cell. Biol. 19, 5495–5503 (1999)

    Article  CAS  Google Scholar 

  13. Sasai, Y., Kageyama, R., Tagawa, Y., Shigemoto, R. & Nakanishi, S. Two mammalian helix–loop–helix factors structurally related to Drosophila hairy and Enhancer of split. Genes Dev. 6, 2620–2634 (1992)

    Article  CAS  Google Scholar 

  14. Jarriault, S. et al. Signalling downstream of activated mammalian Notch. Nature 377, 355–358 (1995)

    Article  ADS  CAS  Google Scholar 

  15. Gekakis, N. et al. Role of the CLOCK protein in the mammalian circadian mechanism. Science 280, 1564–1569 (1998)

    Article  ADS  CAS  Google Scholar 

  16. Iso, T., Kedes, L. & Hamamori, Y. HES and HERP families: multiple effectors of the Notch signaling pathway. J. Cell. Physiol. 194, 237–255 (2003)

    Article  CAS  Google Scholar 

  17. Sui, G. et al. A DNA vector-based RNAi technology to suppress gene expression in mammalian cells. Proc. Natl Acad. Sci. USA 99, 5515–5520 (2002)

    Article  ADS  CAS  Google Scholar 

  18. Lee, Y. et al. Liporegulation in diet-induced obesity. The antisteatotic role of hyperleptinemia. J. Biol. Chem. 276, 5629–5635 (2001)

    Article  CAS  Google Scholar 

  19. Koo, S. H. & Towle, H. C. Glucose regulation of mouse S(14) gene expression in hepatocytes. Involvement of a novel transcription factor complex. J. Biol. Chem. 275, 5200–5207 (2000)

    Article  CAS  Google Scholar 

  20. Michael, L. F., Asahara, H., Shulman, A. I., Kraus, W. L. & Montminy, M. The phosphorylation status of a cyclic AMP-responsive activator is modulated via a chromatin-dependent mechanism. Mol. Cell. Biol. 20, 1596–1603 (2000)

    Article  CAS  Google Scholar 

  21. Hirata, H. et al. Oscillatory expression of the bHLH factor Hes1 regulated by a negative feedback loop. Science 298, 840–843 (2002)

    Article  ADS  CAS  Google Scholar 

  22. Canettieri, G. et al. Attenuation of a phosphorylation-dependent activator by an HDAC–PP1 complex. Nature Struct. Biol. 10, 175–181 (2003)

    Article  CAS  Google Scholar 

  23. Daitoku, H., Yamagata, K., Matsuzaki, H., Hatta, M. & Fukamizu, A. Regulation of PGC-1 promoter activity by protein kinase B and the forkhead transcription factor FKHR. Diabetes 52, 642–649 (2003)

    Article  CAS  Google Scholar 

  24. Takebayashi, K. et al. Structure, chromosomal locus, and promoter analysis of the gene encoding the mouse helix–loop–helix factor HES-1. Negative autoregulation through the multiple N box elements. J. Biol. Chem. 269, 5150–5156 (1994)

    CAS  PubMed  Google Scholar 

  25. Orellana, S. A. & McKnight, G. S. Mutations in the catalytic subunit of cAMP-dependent protein kinase result in unregulated biological activity. Proc. Natl Acad. Sci. USA 89, 4726–4730 (1992)

    Article  ADS  CAS  Google Scholar 

  26. McLarren, K. W. et al. The mammalian basic helix loop helix protein HES-1 binds to and modulates the transactivating function of the runt-related factor Cbfa1. J. Biol. Chem. 275, 530–538 (2000)

    Article  CAS  Google Scholar 

  27. Nakajima, T., Uchida, C., Anderson, S. F., Parvin, J. D. & Montminy, M. Analysis of a cAMP-responsive activator reveals a two-component mechanism for transcriptional induction via signal-dependent factors. Genes Dev. 11, 738–747 (1997)

    Article  CAS  Google Scholar 

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Acknowledgements

We thank K. Suter and L. Vera for performing injections; S. Stifani, R. Kageyama, J. Auwerx, Y. Shi and T. Sudo for providing reagents; and G. Schuetz for CREB knockout mice. We also thank R. Evans for reviewing the manuscript, and I. Verma for support. This work was supported by the NIH (M.M.), the American Diabetes Association, the Hillblom Foundation and the Deutsche Forschungsgemeinschaft (S.H.). F.G. is also supported by Dipartimento di Scienze Biomediche, Università di Sassari, Italy.

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  1. Peptide Biology Laboratories Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, California, 92037-1002, USA

    Stephan Herzig, Susan Hedrick, Ianessa Morantte, Seung-Hoi Koo & Marc Montminy

  2. Laboratory of Genetics, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, California, 92037-1002, USA

    Francesco Galimi

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  1. Stephan Herzig
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Correspondence to Marc Montminy.

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Herzig, S., Hedrick, S., Morantte, I. et al. CREB controls hepatic lipid metabolism through nuclear hormone receptor PPAR-γ. Nature 426, 190–193 (2003). https://doi.org/10.1038/nature02110

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