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An oxysterol signalling pathway mediated by the nuclear receptor LXRα

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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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Authors and Affiliations

  1. Howard Hughes Medical Institute, University of Texas Southwestern Medical Center at Dallas, 5323 Harry Hines Blvd, Dallas, Texas, 75235-9050, USA

    Bethany A. Janowski, Patricia J. Willy, Thota Rama Devi & David J. Mangelsdorf

  2. Department of Pharmacology, Department of Molecular Genetics, University of Texas Southwestern Medical Center at Dallas, 5323 Harry Hines Blvd, Dallas, Texas, 75235-9050, USA

    J. R. Falck

Authors
  1. Bethany A. Janowski
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  2. Patricia J. Willy
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  3. Thota Rama Devi
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  4. J. R. Falck
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  5. David J. Mangelsdorf
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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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