Role of FXR and FTF in bile acid-mediated suppression of cholesterol 7alpha-hydroxylase transcription.

Abstract

Bile acid biosynthesis is subjected to feedback regulation whereby bile acids down-regulate their own synthesis. The major point of this regulation is at the level of cholesterol 7alpha-hydroxylase (7alpha-hydroxylase), which controls bile acid output from the classic pathway. This regulation is at the level of transcription of the gene. Two bile acid response elements have been localized within the 5'-flanking region of the rat gene and these elements overlap three nuclear receptor binding sites for hepatocyte nuclear factor (HNF-4), liver X receptor (LXR) and alpha(1)-fetoprotein transcription factor (FTF). Recently it has been shown that bile acids are physiological ligands for the farnesyl X receptor (FXR), which suggested that FXR could function by binding to one of the three nuclear receptor sites to mediate regulation of 7alpha-hydroxylase transcription by bile acids. In this study we show that FXR is indeed a crucial factor for bile acid-mediated regulation, but that it functions without binding to DNA. Furthermore, we also demonstrate that neither the LXR nor the HNF-4 sites are involved in bile acid-mediated regulation of 7alpha-hydroxylase transcription. Most importantly, we show that the FTF site is essential for regulation of 7alpha-hydroxylase by bile acids, similar to what we have recently demonstrated for another gene of the bile acid biosynthetic pathway, the sterol 12alpha-hydroxylase gene. These studies demonstrate the crucial role of FTF in the expression and regulation of a critical gene in the bile acid biosynthetic pathways.