TY - JOUR
T1 - Regulation of the aldo-keto reductase gene akr1b7 by the nuclear oxysterol receptor LXRα (liver X receptor-α) in the mouse intestine
T2 - Putative role of LXRs in lipid detoxification processes
AU - Volle, David H.
AU - Repa, Joyce J.
AU - Mazur, Andrzej
AU - Cummins, Carolyn L.
AU - Val, Pierre
AU - Henry-Berger, Joelle
AU - Caira, Francoise
AU - Veyssiere, Georges
AU - Mangelsdorf, David J.
AU - Lobaccaro, Jean Marc A
PY - 2004/4
Y1 - 2004/4
N2 - 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.
AB - 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.
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U2 - 10.1210/me.2003-0338
DO - 10.1210/me.2003-0338
M3 - Article
C2 - 14739254
AN - SCOPUS:12144291468
SN - 0888-8809
VL - 18
SP - 888
EP - 898
JO - Molecular Endocrinology
JF - Molecular Endocrinology
IS - 4
ER -