The aldo-keto reductase Akr1b7 gene is a common transcriptional target of xenobiotic receptors pregnane X receptor and constitutive androstane receptor.
Aldo-keto reductase (AKR) family 1, member 7 (AKR1B7), a member of the AKR superfamily, has been suggested to play an important role in the detoxification of lipid peroxidation by-products. The nuclear receptors pregnane X receptor (PXR) and constitutive androstane receptor (CAR) are xenosensors postulated to alleviate xeno- and endobiotic chemical insults. In this study, we show that the mouse Akr1b7 is a shared transcriptional target of PXR and CAR in the liver and intestine. Treatment of wild-type mice with the PXR agonist pregnenolone-16alpha-carbonitrile (PCN) activated Akr1b7 gene expression, whereas the effect was abrogated in PXR(-/-) mice. Similarly, the activation of Akr1b7 gene expression by the CAR agonist 1,4-bis[2-(3,5-dichlorpyridyloxyl)]-benzene, seen in wild-type mice, was abolished in CAR(-/-) mice. The promoter of Akr1b7 gene was activated by PXR and CAR, and this activation was achieved through the binding of PXR-retinoid X receptor (RXR) or CAR-RXR heterodimers to direct repeat-4 type nuclear receptor-binding sites found in the Akr1b7 gene promoter. At the functional level, treatment with PCN in wild-type mice, but not PXR(-/-) mice, led to a decreased intestinal accumulation of malondialdehyde, a biomarker of lipid peroxidation. The regulation of Akr1b7 by PXR was independent of the liver X receptor (LXR), another nuclear receptor known to regulate this AKR isoform. Because a major function of Akr1b7 is to detoxify lipid peroxidation, the PXR-, CAR-, and LXR-controlled regulatory network of Akr1b7 may have contributed to alleviate toxicity associated with lipid peroxidation.
Liu
Ming-Jie
MJ
Center for Pharmacogenetics, University of Pittsburgh, Pittsburgh, PA 15261, USA.
Takahashi
Yuki
Y
Wada
Taira
T
He
Jinhan
J
Gao
Jie
J
Tian
Yanan
Y
Li
Song
S
Xie
Wen
W
D000449:Aldehyde Reductase / Q000235:genetics*; D000818:Animals; D000090702:Constitutive Androstane Receptor; D005786:Gene Expression Regulation; D015227:Lipid Peroxidation; D051379:Mice; D008817:Mice, Mutant Strains; D000077297:Pregnane X Receptor; D011401:Promoter Regions, Genetic; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism*; D011987:Receptors, Steroid / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D020218:Response Elements; D014158:Transcription, Genetic
D000090702:Constitutive Androstane Receptor; D000077297:Pregnane X Receptor; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; C066498:Akr1b7 protein, mouse; D000449:Aldehyde Reductase