Liver X receptor α interferes with SREBP1c-mediated Abcd2 expression: Novel cross-talk in gene regulation

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

Research output: Contribution to journalArticle

32 Scopus citations

Abstract

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 LXRα and SREBP1c. In cell culture, SREBP1c-mediated Abcd2 induction is counteracted by ligand-activated LXRα. Finally, hepatic Abcd2 expression in LXRα,β-deficient mice is inducible to levels vastly exceeding wild type. Together, we identify LXRα as negative modulator of Abcd2, acting through a novel regulatory mechanism involving overlapping SREBP and LXRα binding sites.

Original languageEnglish (US)
Pages (from-to)41243-41251
Number of pages9
JournalJournal of Biological Chemistry
Volume280
Issue number50
DOIs
StatePublished - Dec 16 2005

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Weinhofer, I., Kunze, M., Rampler, H., Bookout, A. L., Forss-Petter, S., & Berger, J. (2005). Liver X receptor α interferes with SREBP1c-mediated Abcd2 expression: Novel cross-talk in gene regulation. Journal of Biological Chemistry, 280(50), 41243-41251. https://doi.org/10.1074/jbc.M509450200