Nucleic Acids Research, 2001, Vol. 29, No. 19 4035-4042
© 2001 Oxford University Press
Suppression of sterol 12
-hydroxylase transcription by the short heterodimer partner: insights into the repression mechanism
Department of Biochemistry and Molecular Biophysics, Medical College of Virginia, PO Box 980614, Richmond, VA 23298-0614, USA
Cholesterol conversion to bile acids is subject to a feedback regulatory mechanism by which bile acids down-regulate their own synthesis. This regulation occurs at the level of transcription of several genes encoding enzymes in the bile acid biosynthetic pathway. One of these enzymes is sterol 12
-hydroxylase/CYP8B1 (12-hydroxylase), the specific enzyme required for cholic acid synthesis. The levels of this enzyme determine the ratio of cholic acid to chenodeoxycholic acid and thus the hydrophobicity of the circulating bile acid pool. Previous studies from this laboratory showed that fetoprotein transcription factor (FTF) is required for 12-hydroxylase promoter activity and bile acid-mediated regulation. Here, we report that the short heterodimer partner (SHP) suppresses 12-hydroxylase promoter activity via an interaction with FTF. Hepatic nuclear factor-4 (HNF-4) binds and activates the 12-hydroxylase promoter and is required for 12-hydroxylase promoter activity. Although HNF-4 interacts with SHP, it is not involved in SHP-mediated suppression of 12-hydroxylase promoter activity. FTF and not HNF-4 is the factor involved in regulation of 12-hydroxylase promoter activity by bile acids through its interaction with SHP. Finally, interaction of SHP with FTF displaces FTF binding to its sites within the 12-hydroxylase promoter. These results provide insights into the mechanism of action of bile acid-mediated regulation of sterol 12-hydroxylase transcription.
* To whom correspondence should be addressed. Tel: +1 804 828 0140; Fax: +1 804 828 0676; Email: ggil{at}vcu.edu
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