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J. Biol. Chem., Vol. 280, Issue 50, 41243-41251, December 16, 2005

This Article Full Text Full Text (PDF) All Versions of this Article: 280/50/41243    most recent M509450200v1 Submit a Letter to Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Weinhofer, I. Articles by Berger, J. Search for Related Content PubMed PubMed Citation Articles by Weinhofer, I. Articles by Berger, J. Social Bookmarking                      What's this?

Liver X Receptor Interferes with SREBP1c-mediated Abcd2 Expression

NOVEL CROSS-TALK IN GENE REGULATION^*

Isabelle Weinhofer, Markus Kunze, Heidelinde Rampler, Angie L. Bookout, Sonja Forss-Petter, and Johannes Berger1

From the Center for Brain Research, Medical University Vienna, A-1090 Vienna, Austria and the Howard Hughes Medical Institute and Department of Pharmacology, University of Texas, Dallas, Texas 75390

The peroxisomal ATP binding cassette (ABC) transporter adrenoleukodystrophy-related protein, encoded by ABCD2, displays functional redundancy with the X-linked adrenoleukodystrophy-associated protein, making ABCD2 up-regulation of therapeutic value. Cholesterol lowering activates human ABCD2 in cultured cells. To investigate in vivo regulation by sterols, we first characterized a sterol regulatory element (SRE) in the murine Abcd2 promoter that is directly bound by SRE-binding proteins (SREBPs). Intriguingly, this element overlaps with a direct repeat 4, which serves as binding site for liver X receptor (LXR)/retinoid X receptor heterodimers, suggesting novel cross-talk between SREBP and LXR/retinoid X receptor in gene regulation. Using fasting-refeeding and cholesterol loading, SREBP accessibility to the SRE/direct repeat 4 was tested. Results suggest that adipose Abcd2 is induced by SREBP1c, whereas hepatic Abcd2 expression is down-regulated by concurrent activation of LXR and SREBP1c. In cell culture, SREBP1c-mediated Abcd2 induction is counteracted by ligand-activated LXR. Finally, hepatic Abcd2 expression in LXR,-deficient mice is inducible to levels vastly exceeding wild type. Together, we identify LXR as negative modulator of Abcd2, acting through a novel regulatory mechanism involving overlapping SREBP and LXR binding sites.

Received for publication, August 26, 2005 , and in revised form, October 20, 2005.

^* This study was supported by a grant from the European Association against Leukodystrophies (ELA, Nancy, France), the Myelin Project, and European Union Project"X-ALD"LSHM-CT2004-502989. 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 To whom correspondence should be addressed: Center for Brain Research, Medical University Vienna, Spitalgasse 4, A-1090 Vienna, Austria. Tel.: 43-1-4277-62812; Fax: 43-1-4277-9628; E-mail: johannes.berger{at}meduniwien.ac.at.

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