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First published on November 16, 2007; DOI: 10.1124/mol.107.039099

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Received for publication June 18, 2007.
Revised November 14, 2007.
Accepted for publication November 15, 2007.

REGULATION OF HUMAN 3{alpha}-HYDROXYSTEROID DEHYDROGENASE (AKR1C4) EXPRESSION BY THE LIVER X RECEPTOR {alpha}

Keith R Stayrook 1, Pamela M Rogers 2, Rajesh S Savkur 1, Yongjun Wang 2, Chen Su 1, Gabor Varga 1, Xin Bu 1, Tao Wei 1, Sunil Nagpal 1, Xiaole Shirley Liu 3, Thomas P Burris 4*

1 Lilly Research Labs 2 Pennington Biomedical Research Center 3 Dana-Farber Cancer Institute 4 Pennington Biomedical Research Center / Louisiana State University

* Address correspondence to: E-mail: thomas.burris{at}pbrc.edu

Abstract

Type I human hepatic 3{alpha}-hydroxysteroid dehydrogenase (3{alpha}-HSD; AKR1C4) plays a significant role in bile acid biosynthesis, steroid hormone metabolism and xenobiotic metabolism. Utilization of a hidden markov model (HMM) for predictive modeling of nuclear hormone receptor response elements coupled with chromatin immunoprecipitation (ChIP)/microarray technology revealed a putative binding site in the AKR1C4 promoter for the nuclear hormone receptor, liver X receptor {alpha}, (LXR{alpha}[NR1H3]), which is the physiological receptor for oxidized cholesterol metabolites. The putative LXR{alpha} response element (LXRE), identified by chromatin immunoprecipitation, was ~1.5 kb upstream of the transcription start site. LXR{alpha} was shown to bind specifically to this LXRE and mediate transcriptional activation of the AKR1C4 gene leading to increased AKR1C4 protein expression. These data suggest that LXR{alpha} may modulate the bile acid biosynthetic pathway at a unique site downstream of CYP7A1 and may also modulate the metabolism of steroid hormones and certain xenobiotics.


Key words: PPARs, Regulation - transcriptional, Regulation - xenobiotic, Cholesterol metabolism/lipoproteins


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