A regulatory cascade of the nuclear receptors FXR, SHP-1, and LRH-1 represses bile acid biosynthesis

Bile acids repress the transcription of cytochrome P450 7A1 (CYP7A1), which catalyzes the rate-limiting step in bile acid biosynthesis. Although bile acids activate the farnesoid X receptor (FXR), the mechanism underlying bil e acid-mediated repression of CYP7A1 remained unclear. We have used a poten t, nonsteroidal FXR ligand to show that FXR induces expression of small het erodimer partner 1 (SHP-1), an atypical member of the nuclear receptor fami ly that lacks a DNA-binding domain. SHP-1 represses expression of CYP7A1 by inhibiting the activity of liver receptor homolog 1 (LRH-1), an orphan nuc lear receptor that is known to regulate CYP7A1 expression positively. This bile acid-activated regulatory cascade provides a molecular basis for the c oordinate suppression of CYP7A1 and other genes involved in bile acid biosy nthesis.