Our findings demonstrate potent bile acid-mediated suppression of hepatic CSAD mRNA levels and induction with cholestyramine-induced enterohepatic bile acid depletion (Fig. 2b). Higher CSAD mRNA abundance with cholestyramine feeding suggests that, under physiological conditions, enterohepatic bile acids exert tonic suppression of CSAD mRNA levels and that CSAD mRNA is not simply suppressed by bile acids at supraphysiologic concentrations. Though we did not directly measure the impact of cholesterol

feeding on hepatic CSAD selleck screening library mRNA levels, the lack of response to LXR agonist treatment (T-0901317) (Fig. 5c) suggests that alterations in cholesterol flux likely would not regulate CSAD mRNA via LXR at the transcriptional level. Farnesoid X receptor and SHP play a canonical role AZD2014 chemical structure in regulating cholate synthesis.[1] Physiological activation of FXR by enterohepatic bile acids induces expression of SHP, which in turn binds to the orphan nuclear receptors LHR-1 and HNF4α, and potentially other promoter-bound elements, inhibiting transcription of CYP7A1.[1] Previous studies have demonstrated that CYP7A1 gene expression is decreased by FXR agonist treatment[24] and is higher in both Fxr−/− and Shp−/− mice[2, 7, 8, 24] in which the feedback loop has been genetically disrupted. In the current study, we utilize both pharmacological and genetic approaches to establish that SHP and FXR are also key components

of bile acid-mediated suppression of CSAD mRNA level. A role for FXR was established by the finding that GW4064, a FXR agonist, potently suppresses hepatic CSAD mRNA levels (Fig. 3a). A role for SHP in this feedback loop was established by the finding that CSAD abundance is dramatically increased in Shp−/− mice (Fig. 4a). Taken together, these results demonstrate that hepatic CSAD mRNA abundance else is regulated through genetic mechanisms shared with CYP7A1 (Fig. 6). Though FXR and SHP are central to CYP7A1 gene expression, the existence of an SHP-independent pathway has been demonstrated by using Shp−/− mice.[7,

8] This is now understood to include the FGF15/19 pathway and signaling via FGFR4/β-klotho with activation of c-Jun N-terminal kinase[9, 25] and transcriptional repression of CYP7A1. Inagaki et al. showed that the FGF15/FGFR4 signaling cooperates with SHP to repress CYP7A1 in liver although FGF19 reduced CYP7A1 mRNA levels without increasing SHP mRNA levels[9] indicating that the FXR/FGF19 pathway is also SHP-independent. The current findings indicate that hepatic CSAD mRNA level is not regulated by FGF19 administration despite potent suppression of CYP7A1 level (Fig. 5a). In addition, activation of LXR did not result in altered hepatic CSAD mRNA abundance. This divergence in response implies that while CYP7A1 and CSAD mRNA respond similarly to dietary bile acid supplementation, and are both regulated by FXR and SHP, there are important differences in some of the mediators involved.