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Originally published In Press as doi:10.1074/jbc.M303913200 on July 2, 2003

J. Biol. Chem., Vol. 278, Issue 38, 36418-36429, September 19, 2003
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Estrogen Receptor {alpha} Regulates Expression of the Orphan Receptor Small Heterodimer Partner*,

KehDih Lai, Douglas C. Harnish and Mark J. Evans {ddagger}

From the Wyeth Research, Collegeville, Pennsylvania 19426

Hormonal status can influence diverse metabolic pathways. Small heterodimer partner (SHP) is an orphan nuclear receptor that can modulate the activity of several transcription factors. Estrogens are here shown to directly induce expression of the SHP in the mouse and rat liver and in human HepG2 cells. SHP is rapidly induced within 2 h following treatment of mice with ethynylestradiol (EE) or the estrogen receptor {alpha} (ER{alpha})-selective compound propyl pyrazole triol (PPT). SHP induction by these estrogens is completely absent in ER{alpha}KO mice. Mutation of the human SHP promoter defined HNF-3, HNF-4, GATA, and AP-1 sites as important for basal activity, whereas EE induction required two distinct elements located between –309 and –267. One of these elements contains an estrogen response element half-site that bound purified ER{alpha}, and ER{alpha} with a mutated DNA binding domain was unable to stimulate SHP promoter activity. This ER{alpha} binding site overlaps the known farnesoid X receptor (FXR) binding site in the SHP promoter, and the combination of EE plus FXR agonists did not produce an additive induction of SHP expression in mice. Surprisingly, induction of SHP by EE did not inhibit expression of the known SHP target genes cholesterol 7{alpha}-hydroxylase (CYP7A1) or sterol 12{alpha}-hydroxylase (CYP8B1). However, the direct regulation of SHP expression may provide a basis for some of the numerous biological effects of estrogens.

Received for publication, April 14, 2003 , and in revised form, July 1, 2003.

* 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.

The on-line version of this article (available at http://www.jbc.org) contains Supplemental Table SII.

{ddagger} To whom correspondence should be addressed: Wyeth Research, 500 Arcola Rd., Collegeville, PA 19426. Tel.: 484-865-5538; Fax: 484-865-9394; E-mail: Evansm{at}wyeth.com.


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