Abstract
CHOLESTEROL and its oxysterol congeners are important constitu-ents of cell membranes and function as intermediates in several crucial biosynthetic pathways. These compounds autoregulate their metabolic fate by end-product repression and activation of downstream catabolism1. Although end-product repression by oxysterols is relatively well understood2, the mechanism by which these compounds act as positive transcription signalling molecules is unknown. Here we identify a specific group of endogenous oxysterols that activate transcription through the nuclear receptor LXRα. Transactivation of LXRα by oxysterols occurs at concentrations at which these compounds exist in vivo. The most potent activators also serve as intermediary substrates in the rate-limiting steps of three important metabolic pathways: steroid hormone biosynthesis, bile acid synthesis, and conversion of lanosterol to cholesterol. Our results demonstrate the existence of a nuclear receptor signalling pathway for oxysterols and suggest that LXRα may be important as a sensor of cholesterol metabolites.
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References
Russell, D. W. Cardiovasc. Drugs Ther. 6, 103–110 (1992).
Wang, X., Sato, R., Brown, M. S., Hua, X. & Goldstein, J. L. Cell 77, 53–62 (1994).
Willy, P. J. et al. Genes Dev. 9, 1033–1045 (1995).
Heyman, R. A. et al. Cell 68, 397–406 (1992).
Harmon, M. A., Boehm, M. F., Heyman, R. A. & Mangelsdorf, D. J. Proc. Natl Acad. Sci. USA 92, 6157–6160 (1995).
Byskov, A. G. et al. Nature 374, 559–562 (1995).
Kandutsch, A. A., Chen, H. W. & Heiniger, H.-J. Science 201, 498–501 (1978).
Dhar, A. K., Teng, J. I. & Smith, L. L. J. Neurochem. 21, 51–60 (1973).
Javitt, N. B., Kob, E., Burstein, S., Cohen, B. & Kutscher, J. J. Biol. Chem. 256, 12644–12646 (1981).
Dixon, R., Furutachi, T. & Lieberman, S. Biochem. Biophys. Res. Commun. 40, 161–165 (1970).
Forman, B. M. et al. Cell 81, 687–693 (1995).
Forman, B. M. et al. Cell 83, 803–812 (1995).
Kliewer, S. A. et al. Cell 83, 813–819 (1995).
Song, C., Kokontis, J. M., Hiipakka, R. A. & Liao, S. Proc. Natl Acad. Sci. USA 91, 10809–10813 (1994).
Ikekawa, N. in Sterols and Bile Acids (eds Danielsson, H. & Sjövall, J.) 199–230 (Elsevier/North Holland Biomedical, Amsterdam, 1985).
Yao, T. -P., Segraves, W. A., Oro, A. E., McKeown, M. & Evans, R. M. Cell 71, 63–72 (1992).
Mangelsdorf, D. J. et al. Cell 83, 835–839 (1995).
Kliewer, S. A., Umesono, K., Noonan, D. J., Heyman, R. A. & Evans, R. M. Nature 358, 771–774 (1992).
Leng, X., Tsai, S. Y., O'Malley, B. W. & Tsai, M. J. J. Steroid Biochem. Mol. Biol. 46, 643–661 (1993).
Hörlein, A. J. et al. Nature 377, 397–404 (1995).
Chen, J. D. & Evans, R. M. Nature 377, 454–457 (1995).
Oñate, S. A., Tsai, S. Y., Tsai, M. J. & O'Malley, B. W. Science 270, 1354–1357 (1995).
Dolle, R. E., Schmidt, S. J., Erhard, K. F. & Kruse, L. J. Am. Chem. Soc. 111, 278–284 (1989).
Morisaki, M., Sato, S. & Ikekawa, N. Chem. Pharmacol. Bull. 25, 2576–2583 (1977).
Mangelsdorf, D. J., Ong, E. S., Dyck, J. A. & Evans, R. M. Nature 345, 224–229 (1990).
Giguère, V., Ong, E. S., Segui, P. & Evans, R. M. Nature 330, 624–629 (1987).
Weinberger, C. et al. Nature 324, 641–646 (1986).
Baker, A. R. et al. Proc. Natl Acad. Sci. USA 85, 3294–3298 (1988).
Issemann, I. & Green, S. Nature 347, 645–650 (1990).
Green, S. et al. Nature 320, 134–139 (1986).
Hollenberg, S. M. et al. Nature 318, 635–641 (1985).
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Janowski, B., Willy, P., Devi, T. et al. An oxysterol signalling pathway mediated by the nuclear receptor LXRα. Nature 383, 728–731 (1996). https://doi.org/10.1038/383728a0
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DOI: https://doi.org/10.1038/383728a0
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