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Regulation of Human 3-Hydroxysteroid Dehydrogenase (AKR1C4) Expression by the Liver X Receptor

Nuclear Receptor Biology Laboratory, Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge, Louisiana (P.M.R., Y.W., T.P.B.); Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, Indiana (K.R.S., R.S.S., X.B., S.N.); Lilly Research Laboratories, Greenfield, Indiana (C.S., G.V.); and Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA (X.S.L.)

Type I human hepatic 3-hydroxysteroid dehydrogenase (AKR1C4) plays a significant role in bile acid biosynthesis, steroid hormone metabolism, and xenobiotic metabolism. Utilization of a hidden Markov model for predictive modeling of nuclear hormone receptor response elements coupled with chromatin immunoprecipitation/microarray technology revealed a putative binding site in the AKR1C4 promoter for the nuclear hormone receptor known as liver X receptor , (LXR [NR1H3]), which is the physiological receptor for oxidized cholesterol metabolites. The putative LXR response element (LXRE), identified by chromatin immunoprecipitation, was 1.5 kilobase pairs upstream of the transcription start site. LXR 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 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.

Address correspondence to: Dr. Thomas P. Burris, PBRC/LSU, 6400 Perkins Rd, Baton Rouge LA 70808. E-mail: thomas.burris{at}pbrc.edu

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