The nuclear receptor LXR is a glucose sensor (original) (raw)

Nature volume 445, pages 219–223 (2007)Cite this article

Abstract

The liver has a central role in glucose homeostasis, as it has the distinctive ability to produce and consume glucose1. On feeding, glucose influx triggers gene expression changes in hepatocytes to suppress endogenous glucose production and convert excess glucose into glycogen or fatty acids to be stored in adipose tissue2. This process is controlled by insulin, although debate exists as to whether insulin acts directly or indirectly on the liver3. In addition to stimulating pancreatic insulin release, glucose also regulates the activity of ChREBP, a transcription factor that modulates lipogenesis4. Here we describe another mechanism whereby glucose determines its own fate: we show that glucose binds and stimulates the transcriptional activity of the liver X receptor (LXR), a nuclear receptor that coordinates hepatic lipid metabolism. d-Glucose and d-glucose-6-phosphate are direct agonists of both LXR-α and LXR-β. Glucose activates LXR at physiological concentrations expected in the liver and induces expression of LXR target genes with efficacy similar to that of oxysterols, the known LXR ligands. Cholesterol homeostasis genes that require LXR for expression are upregulated in liver and intestine of fasted mice re-fed with a glucose diet, indicating that glucose is an endogenous LXR ligand. Our results identify LXR as a transcriptional switch that integrates hepatic glucose metabolism and fatty acid synthesis.

This is a preview of subscription content, access via your institution

Access options

Subscribe to this journal

Receive 51 print issues and online access

$199.00 per year

only $3.90 per issue

Buy this article

Prices may be subject to local taxes which are calculated during checkout

Additional access options:

Similar content being viewed by others

References

  1. Zierler, K. Whole body glucose metabolism. Am. J. Physiol. 276, E409–E426 (1999)
    CAS PubMed Google Scholar
  2. Moore, M. C., Cherrington, A. D. & Wasserman, D. H. Regulation of hepatic and peripheral glucose disposal. Best Pract. Res. Clin. Endocrinol. Metab. 17, 343–364 (2003)
    Article CAS Google Scholar
  3. Cherrington, A. D. The role of hepatic insulin receptors in the regulation of glucose production. J. Clin. Invest. 115, 1136–1139 (2005)
    Article CAS Google Scholar
  4. Yamashita, H. et al. A glucose-responsive transcription factor that regulates carbohydrate metabolism in the liver. Proc. Natl Acad. Sci. USA 98, 9116–9121 (2001)
    Article ADS CAS Google Scholar
  5. Shulman, A. I. & Mangelsdorf, D. J. Retinoid x receptor heterodimers in the metabolic syndrome. N. Engl. J. Med. 353, 604–615 (2005)
    Article CAS Google Scholar
  6. Schultz, J. R. et al. Role of LXRs in control of lipogenesis. Genes Dev. 14, 2831–2838 (2000)
    Article CAS Google Scholar
  7. Peet, D. J. et al. Cholesterol and bile acid metabolism are impaired in mice lacking the nuclear oxysterol receptor LXRα. Cell 93, 693–704 (1998)
    Article CAS Google Scholar
  8. Janowski, B. A., Willy, P. J., Devi, T. R., Falck, J. R. & Mangelsdorf, D. J. An oxysterol signalling pathway mediated by the nuclear receptor LXRα. Nature 383, 728–731 (1996)
    Article ADS CAS Google Scholar
  9. Joseph, S. B. et al. Synthetic LXR ligand inhibits the development of atherosclerosis in mice. Proc. Natl Acad. Sci. USA 99, 7604–7609 (2002)
    Article ADS CAS Google Scholar
  10. Laffitte, B. A. et al. Activation of liver X receptor improves glucose tolerance through coordinate regulation of glucose metabolism in liver and adipose tissue. Proc. Natl Acad. Sci. USA 100, 5419–5424 (2003)
    Article ADS CAS Google Scholar
  11. Cao, G. et al. Antidiabetic action of a liver x receptor agonist mediated by inhibition of hepatic gluconeogenesis. J. Biol. Chem. 278, 1131–1136 (2003)
    Article CAS Google Scholar
  12. Stehno-Bittel, L., Perez-Terzic, C. & Clapham, D. E. Diffusion across the nuclear envelope inhibited by depletion of the nuclear Ca2+ store. Science 270, 1835–1838 (1995)
    Article ADS CAS Google Scholar
  13. Fehr, M., Lalonde, S., Ehrhardt, D. W. & Frommer, W. B. Live imaging of glucose homeostasis in nuclei of COS-7 cells. J. Fluoresc. 14, 603–609 (2004)
    Article CAS Google Scholar
  14. Shimomura, I. et al. Insulin selectively increases SREBP-1c mRNA in the livers of rats with streptozotocin-induced diabetes. Proc. Natl Acad. Sci. USA 96, 13656–13661 (1999)
    Article ADS CAS Google Scholar
  15. Eberle, D., Hegarty, B., Bossard, P., Ferre, P. & Foufelle, F. SREBP transcription factors: master regulators of lipid homeostasis. Biochimie 86, 839–848 (2004)
    Article CAS Google Scholar
  16. Liang, G. et al. Diminished hepatic response to fasting/refeeding and liver X receptor agonists in mice with selective deficiency of sterol regulatory element-binding protein-1c. J. Biol. Chem. 277, 9520–9528 (2002)
    Article CAS Google Scholar
  17. Repa, J. J. et al. Regulation of mouse sterol regulatory element-binding protein-1c gene (SREBP-1c) by oxysterol receptors, LXRα and LXRα. Genes Dev. 14, 2819–2830 (2000)
    Article CAS Google Scholar
  18. Chen, G., Liang, G., Ou, J., Goldstein, J. L. & Brown, M. S. Central role for liver X receptor in insulin-mediated activation of Srebp-1c transcription and stimulation of fatty acid synthesis in liver. Proc. Natl Acad. Sci. USA 101, 11245–11250 (2004)
    Article ADS CAS Google Scholar
  19. Iizuka, K., Bruick, R. K., Liang, G., Horton, J. D. & Uyeda, K. Deficiency of carbohydrate response element-binding protein (ChREBP) reduces lipogenesis as well as glycolysis. Proc. Natl Acad. Sci. USA 101, 7281–7286 (2004)
    Article ADS CAS Google Scholar
  20. Parks, E. J. Changes in fat synthesis influenced by dietary macronutrient content. Proc. Nutr. Soc. 61, 281–286 (2002)
    Article CAS Google Scholar
  21. Lin, J. et al. Hyperlipidemic effects of dietary saturated fats mediated through PGC-1β coactivation of SREBP. Cell 120, 261–273 (2005)
    Article CAS Google Scholar
  22. Joseph, S. B. et al. LXR-dependent gene expression is important for macrophage survival and the innate immune response. Cell 119, 299–309 (2004)
    Article CAS Google Scholar
  23. Janowski, B. A. et al. Structural requirements of ligands for the oxysterol liver X receptors LXRα and LXRβ. Proc. Natl Acad. Sci. USA 96, 266–271 (1999)
    Article ADS CAS Google Scholar
  24. DeBlasi, A., O’Reilly, K. & Motulsky, H. J. Calculating receptor number from binding experiments using same compound as radioligand and competitor. Trends Pharmacol. Sci. 10, 227–229 (1989)
    Article CAS Google Scholar

Download references

Acknowledgements

We thank S. Bohan, R. Romeo, B. Geierstanger, M. Chalmers, P. Griffin, N. Gekakis, M. Crestani, H. Shimano, T. Matsuzaka, P. Tontonoz, B. Laffitte, S. Joseph, A. Brock, E. Peters and K. Nettles for technical help and/or useful comments. C.G. was a visiting scientist supported by a fellowship from the Department of Pharmacological Sciences, University of Milano, Italy.

Author Contributions L.V., C.G., E.H. and A.K. performed experiments; P.A.M. and V.M. designed and performed experiments and analysed data; and N.M. and E.S. designed and performed experiments, analysed data, and wrote the manuscript.

Author information

Authors and Affiliations

  1. Genomics Institute of the Novartis Research Foundation, 10675 John Hopkins Drive, California, 92121, San Diego, USA
    Nico Mitro, Puiying A. Mak, Leo Vargas, Cristina Godio, Eric Hampton, Valentina Molteni, Andreas Kreusch & Enrique Saez
  2. The Scripps Research Institute, 10550 North Torrey Pines Road, California, 92037, La Jolla, USA
    Nico Mitro & Enrique Saez

Authors

  1. Nico Mitro
    You can also search for this author inPubMed Google Scholar
  2. Puiying A. Mak
    You can also search for this author inPubMed Google Scholar
  3. Leo Vargas
    You can also search for this author inPubMed Google Scholar
  4. Cristina Godio
    You can also search for this author inPubMed Google Scholar
  5. Eric Hampton
    You can also search for this author inPubMed Google Scholar
  6. Valentina Molteni
    You can also search for this author inPubMed Google Scholar
  7. Andreas Kreusch
    You can also search for this author inPubMed Google Scholar
  8. Enrique Saez
    You can also search for this author inPubMed Google Scholar

Corresponding author

Correspondence toEnrique Saez.

Ethics declarations

Competing interests

Reprints and permissions information is available at www.nature.com/reprints. The authors declare no competing financial interests.

Supplementary information

Supplementary Information

This file contains Supplementary Figures 1-10 with legends, Supplementary Methods and Supplementary Table 1. (PDF 962 kb)

Rights and permissions

About this article

Cite this article

Mitro, N., Mak, P., Vargas, L. et al. The nuclear receptor LXR is a glucose sensor.Nature 445, 219–223 (2007). https://doi.org/10.1038/nature05449

Download citation

This article is cited by