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J. Biol. Chem., Vol. 281, Issue 38, 27816-27826, September 22, 2006

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Sterol Intermediates from Cholesterol Biosynthetic Pathway as Liver X Receptor Ligands^*

Chendong Yang, Jeffrey G. McDonald, Amit Patel, Yuan Zhang, Michihisa Umetani, Fang Xu^¶, Emily J. Westover¹, Douglas F. Covey^**, David J. Mangelsdorf^||, Jonathan C. Cohen^¶2, and Helen H. Hobbs^||3

From the Departments of Molecular Genetics and Pharmacology, the ^¶Center for Human Nutrition, and the ^||Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, Texas 75390 and the ^**Department of Molecular Biology and Pharmacology, Washington University School of Medicine, St. Louis, Missouri 63110

The liver X receptors (LXRs) are ligand-activated transcription factors that regulate the expression of genes controlling lipid metabolism. Oxysterols bind LXRs with high affinity in vitro and are implicated as ligands for the receptor. We showed previously that accumulation of selected dietary sterols, in particular stigmasterol, is associated with activation of LXR in vivo. In the course of the defining of structural features of stigmasterol that confer LXR agonist activity, we determined that the presence of an unsaturated bond in the side chain of the sterol was necessary and sufficient for activity, with the C-24 unsaturated cholesterol precursor sterols desmosterol and zymosterol exerting the largest effects. Desmosterol failed to increase expression of the LXR target gene, ABCA1, in LXR/-deficient mouse fibroblasts, but was fully active in cells lacking cholesterol 24-, 25-, and 27-hydroxylase; thus, the effect of desmosterol was LXR-dependent and did not require conversion to a side chain oxysterol. Desmosterol bound to purified LXR and LXR in vitro and supported the recruitment of steroid receptor coactivator 1. Desmosterol also inhibited processing of the sterol response element-binding protein-2 and reduced expression of hydroxymethylglutaryl-CoA reductase. These observations are consistent with specific intermediates in the cholesterol biosynthetic pathway regulating lipid homeostasis through both the LXR and sterol response element-binding protein pathways.

Received for publication, April 20, 2006 , and in revised form, July 17, 2006.

^* This work was supported in part by National Institutes of Health Grants HL20948, HL72304, GM47969, and GM069338. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Supported by National Institutes of Health Training Grant T32 HL07275.

² To whom correspondence may be addressed. E-mail: jonathan.cohen{at}utsouthwestern.edu. ³ To whom correspondence may be addressed. E-mail: helen.hobbs{at}utsouthwestern.edu.

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