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The nuclear receptor LXR is a glucose sensor


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.

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Figure 1: Glucose induces LXR transcriptional activity.
Figure 2: Glucose is a direct LXR agonist.
Figure 3: Glucose displaces a labelled high-affinity LXR ligand.
Figure 4: Glucose regulates direct LXR target genes in vivo.


  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)

    CAS  Article  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)

    CAS  Article  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)

    ADS  CAS  Article  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)

    CAS  Article  Google Scholar 

  6. Schultz, J. R. et al. Role of LXRs in control of lipogenesis. Genes Dev. 14, 2831–2838 (2000)

    CAS  Article  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)

    CAS  Article  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)

    ADS  CAS  Article  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)

    ADS  CAS  Article  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)

    ADS  CAS  Article  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)

    CAS  Article  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)

    ADS  CAS  Article  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)

    CAS  Article  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)

    ADS  CAS  Article  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)

    CAS  Article  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)

    CAS  Article  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)

    CAS  Article  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)

    ADS  CAS  Article  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)

    ADS  CAS  Article  Google Scholar 

  20. Parks, E. J. Changes in fat synthesis influenced by dietary macronutrient content. Proc. Nutr. Soc. 61, 281–286 (2002)

    CAS  Article  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)

    CAS  Article  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)

    CAS  Article  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)

    ADS  CAS  Article  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)

    CAS  Article  Google Scholar 

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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.

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Correspondence to Enrique Saez.

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

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Mitro, N., Mak, P., Vargas, L. et al. The nuclear receptor LXR is a glucose sensor. Nature 445, 219–223 (2007).

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