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Regulation of the Aldo-Keto Reductase Gene akr1b7 by the Nuclear Oxysterol Receptor LXR (Liver X Receptor-) in the Mouse Intestine: Putative Role of LXRs in Lipid Detoxification Processes

Physiologie Comparée et Endocrinologie Moléculaire (D.H.V., P.V., J.H.-B., F.C., G.V., J.-M.A.L.), Unité Mixte de Recherche, Centre National de la Recherche Scientifique 6547, 63177 Aubière, France; Department of Pharmacology and Howard Hughes Medical Institute (J.J.R., C.L.C., D.J.M.), University of Texas Southwestern Medical Center, Dallas, Texas 75390-9050; and Unité Maladies Métaboliques et Micronutriments (A.M.), Institut National de la Recherche Agronomique, 63122 Saint-Genès-Champanelle, France

Address all correspondence and requests for reprints to: Jean-Marc A. Lobaccaro, Unité Mixte de Recherche, Centre National de la Recherche Scientifique 6547-Université Blaise Pascal, 24 avenue des Landais, 63177 Aubière Cedex, France. E-mail: j-marc.lobaccaro{at}geem.univ-bpclermont.fr.

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 LXR 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.

NURSA Molecule Pages Link:

Nuclear Receptors:   LXRβ  |  LXRα  |  RXRα

Ligands:   LGD 100268  |  22α-Hydroxycholesterol  |  T0901317  |  9-cis-Retinoic acid

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