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Molecular Endocrinology, doi:10.1210/me.2002-0246
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Molecular Endocrinology 17 (3): 386-394
Copyright © 2003 by The Endocrine Society

Differential Regulation of Rat and Human CYP7A1 by the Nuclear Oxysterol Receptor Liver X Receptor-{alpha}

Bryan Goodwin, Michael A. Watson, Hwajin Kim, Ji Miao, Jongsook Kim Kemper and Steven A. Kliewer

Nuclear Receptor Discovery Research (B.G., M.A.W.), GlaxoSmithKline Research and Development, Research Triangle Park, North Carolina 27709; Department of Molecular & Integrative Physiology (H.K., J.M., J.K.K.), University of Illinois at Urbana-Champaign, Urbana, Illinois 61801; and Department of Molecular Biology (S.A.K.), University of Texas Southwestern Medical Center, Dallas, Texas 75390-8594

Address all correspondence and requests for reprints to: Bryan Goodwin, Nuclear Receptor Discovery Research, GlaxoSmithKline Research and Development, Research Triangle Park, North Carolina 27709, E-mail: bryan.j.goodwin{at}gsk.com, and/or Steven A. Kliewer, Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, Texas 75390-8594. E-mail: steven.kliewer{at}utsouthwestern.edu.

In rodent liver, transcription of the gene encoding cholesterol 7{alpha}-hydroxylase (CYP7A1), which catalyzes the rate-limiting step in the classic bile acid synthetic pathway, is stimulated by the liver X receptor {alpha} (LXR{alpha}), a nuclear receptor for oxysterol metabolites of cholesterol. This feed-forward regulatory loop provides a mechanism for the elimination of excess cholesterol from the body. In this report, we demonstrate that in primary cultures of human hepatocytes, activation of LXR{alpha} has the opposite effect, repressing CYP7A1 expression. This repression is mediated, at least in part, through induction of the orphan nuclear receptor, short heterodimer partner (SHP), which is also induced by bile acids. We demonstrate that SHP is regulated directly by LXR{alpha} through a DNA response element that overlaps with the previously characterized bile acid response element. Our data reveal a fundamental difference in the regulation of CYP7A1 in rodent and human hepatocytes and provide evidence that different species employ distinct molecular strategies to regulate cholesterol homeostasis.

NURSA Molecule Pages Link:

Nuclear Receptors:   SHP  |  LXRα  |  FXRα  |  RXRα
Ligands:   LGD 100268  |  22α-Hydroxycholesterol  |  GW4064  |  T0901317



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