Regulation of the aldo-keto reductase gene akr1b7 by the nuclear oxysterol receptor LXRα (liver X receptor-α) in the mouse intestine: Putative role of LXRs in lipid detoxification processes

David H. Volle, Joyce J. Repa, Andrzej Mazur, Carolyn L. Cummins, Pierre Val, Joelle Henry-Berger, Francoise Caira, Georges Veyssiere, David J. Mangelsdorf, Jean Marc A Lobaccaro

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Abstract

Liver X receptors (LXRs) regulate the expression of a number of genes involved in cholesterol and lipid metabolism after activation by their cognate oxysterol ligands. AKR1-B7 (aldo-keto reductase 1-B7) is expressed in LXR target tissues such as intestine, and because of its known role in detoxifying lipid peroxides, we investigated whether the AKR1-B7 detoxification pathway was regulated by LXRs. Here we show that synthetic LXR agonists increase the accumulation of AKR1-B7 mRNA and protein levels in mouse intestine in wild-type but not lxr-/- mice. Regulation of akr1b7 by retinoic X receptor/LXR heterodimers is dependent on three response elements in the proximal murine akr1b7 promoter. Two of these cis-acting elements are specific for regulation by the LXRα isoform. In addition, in duodenum of wild-type mice fed a synthetic LXR agonist, we observed an LXR-dependent decrease in lipid peroxidation. Our results demonstrate that akr1b7 is a direct target of LXRs throughout the small intestine, and that LXR activation plays a protective role by decreasing the deleterious effects of lipid peroxides in duodenum. Taken together, these data suggest a new role for LXRs in lipid detoxification.

Original languageEnglish (US)
Pages (from-to)888-898
Number of pages11
JournalMolecular Endocrinology
Volume18
Issue number4
DOIs
StatePublished - Apr 2004

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ASJC Scopus subject areas

  • Molecular Biology
  • Endocrinology, Diabetes and Metabolism

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