ABSTRACT
Bile acid homeostasis is critical in maintaining health and is primarily regulated by the nuclear receptors farnesoid X receptor (FXR) and small heterodimer partner (SHP). Bile acid-activated FXR indirectly inhibits expression of cholesterol 7α hydroxylase (CYP7A1), a key enzyme in conversion of cholesterol to bile acids, by induction of SHP. We recently demonstrated that SHP inhibits CYP7A1 transcription by recruiting chromatin-modifying cofactors, including Brm-Swi/Snf. Swi/Snf complexes contain either Brm or Brg-1 ATPases, and whether these subunits have distinct functions remains unclear. We have examined the role of these subunits in regulation of bile acid metabolism under physiological conditions by FXR and SHP. Brg-1 interacted with FXR and enhanced FXR-mediated transactivation of SHP, whereas Brm interacted with SHP and enhanced SHP-mediated repression of CYP7A1 and, interestingly, auto-repression of SHP. Chromatin immunoprecipitation and remodeling studies revealed that after treatment with FXR agonists, Brg-1 was recruited to the SHP promoter, resulting in transcriptionally active accessible chromatin, whereas Brm was recruited to both CYP7A1 and SHP promoters, resulting in inactive inaccessible chromatin. Our studies demonstrate that Brm and Brg-1 have distinct functions in the regulation of two key genes, CYP7A1 and SHP, within a single physiological pathway, feedback inhibition of bile acid biosynthesis, by differentially targeting SHP and FXR.
Structural analysis of the gene encoding rat cholesterol alpha-hydroxylase, the key enzyme for bile acid biosynthesis.
