Abstract
Cholesterol conversion to bile acids occurs via the "classic" (neutral) or the "alternative" (acidic) bile acid biosynthesis pathways. Sterol 12alpha-hydroxylase/CYP8b1 is 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. Expression of the 12alpha-hydroxylase gene is tightly down-regulated by hydrophobic bile acids. In this study, we report the characterization of two DNA elements that are required for both the 12alpha-hydroxylase promoter activity and bile acid-mediated regulation. Mutation of these elements suppresses 12alpha-hydroxylase promoter activity. Mutations of any other part of the promoter do not alter substantially the promoter activity or alter regulation by bile acids relative to the wild type promoter. These two DNA elements bind alpha(1)-fetoprotein transcription factor (FTF), a member of the nuclear receptor family. We also show that overexpression of FTF in a non-liver cell line activates the sterol 12alpha-hydroxylase promoter. These studies demonstrate the crucial role of FTF for the expression and regulation of a critical gene in the bile acid biosynthetic pathways.
Highlights
IntroductionCholesterol conversion to bile acids occurs via the “classic” (neutral) or the “alternative” (acidic) bile acid biosynthesis pathways
Cholesterol conversion to bile acids occurs via the “classic” or the “alternative” bile acid biosynthesis pathways
Cells were treated with or without 100 mM chenodeoxycholic acid (CDCA), which was shown to suppress expression of the endogenous gene in primary hepatocytes, mimicking the bile acid-mediated regulation that has been described in vivo [18]
Summary
Cholesterol conversion to bile acids occurs via the “classic” (neutral) or the “alternative” (acidic) bile acid biosynthesis pathways. Sterol 12a-hydroxylase/CYP8b1 is the specific enzyme required for cholic acid synthesis The levels of this enzyme determine the ratio of cholic acid to chenodeoxycholic acid and the hydrophobicity of the circulating bile acid pool. We show that overexpression of FTF in a non-liver cell line activates the sterol 12a-hydroxylase promoter These studies demonstrate the crucial role of FTF for the expression and regulation of a critical gene in the bile acid biosynthetic pathways. Sterol 12a-hydroxylase/CYP8b1 (12a-hydroxylase) is the specific enzyme for cholic acid synthesis and determines the ratio of cholic acid to chenodeoxycholic acid and the hydrophobicity of the circulating pool. Because chenodeoxycholic acid is a more potent suppressor of HMG-CoA reductase and 7a-hydroxylase than cholic acid [3, 4], the relative activity of 12a-hydroxylase may play an important role in the regulation of hepatic cholesterol homeostasis. The molecular mechanisms involved in that regulation are not well defined
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
