Regulation of the aldo-keto reductase gene akr1b7 by the nuclear oxysterol receptor LXRalpha (liver X receptor-alpha) in the mouse intestine: putative role of LXRs in lipid detoxification processes.
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 LXRalpha 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.
Volle
David H
DH
Physiologie Comparée et Endocrinologie Moléculaire, Unité Mixte de Recherche, Centre National de la Recherche Scientifique 6547-Université Blaise Pascal, 24 avenue des Landais, 63177 Aubière Cedex, France.
Repa
Joyce J
JJ
Mazur
Andrzej
A
Cummins
Carolyn L
CL
Val
Pierre
P
Henry-Berger
Joelle
J
Caira
Francoise
F
Veyssiere
Georges
G
Mangelsdorf
David J
DJ
Lobaccaro
Jean-Marc A
JM
D000449:Aldehyde Reductase / Q000096:biosynthesis / Q000235:genetics*; D000818:Animals; D001665:Binding Sites; D004268:DNA-Binding Proteins; D005786:Gene Expression Regulation / Q000502:physiology*; D007413:Intestinal Mucosa / Q000378:metabolism; D050356:Lipid Metabolism; D008055:Lipids / Q000633:toxicity; D000071518:Liver X Receptors; D051379:Mice; D018345:Mice, Knockout; D057093:Orphan Nuclear Receptors; D011401:Promoter Regions, Genetic; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists / Q000235:genetics / Q000378:metabolism*
D004268:DNA-Binding Proteins; D008055:Lipids; D000071518:Liver X Receptors; C000605214:Nr1h3 protein, mouse; D057093:Orphan Nuclear Receptors; D018160:Receptors, Cytoplasmic and Nuclear; C066498:Akr1b7 protein, mouse; D000449:Aldehyde Reductase