We also investigated whether pharmacological interventions that modulated

hepatic CSAD mRNA abundance also mediated changes in renal CSAD mRNA abundance. We found that FXR agonist treatment did not alter CSAD abundance in kidney. Furthermore, renal CSAD abundance was not altered in Shp−/− mice. These data suggest that there are liver-specific regulatory components controlling hepatic CSAD response to bile acids, and that these are possibly missing or differentially regulated in kidney. It will be PARP inhibitor interesting to examine candidate liver-specific components for CSAD transcriptional regulation because both FXR and SHP (though at low levels) are expressed in kidney.[40, 41] The possibility

of extrahepatic CSAD regulation by FXR agonists should be kept in mind as human clinical trials are underway using pharmacological FXR agonists. Bile acid CoA:amino-acid N-acyltransferase and BACS, two enzymes involved in bile acid conjugation to taurine and glycine, have been demonstrated to undergo FXR-dependent regulation via a promoter inverted repeat (IR-1)[16] In the present study, we observed that this website pharmacological FXR agonist activation reduced hepatic BAT but not BACS mRNA expression. In addition, BAT and BACS mRNA abundance were similar in WT and Shp−/− mice. Taken together, these data suggest that BAT and BACS are not potently regulated by nuclear receptors SHP and FXR and neither gene appears to be regulated in tandem with CSAD. We were surprised to find that, despite a more than eightfold elevation CSAD in Shp−/− mice, hepatic hypotaurine was only 2–3-fold elevated, and hepatic taurine content did not differ from WT controls. Furthermore, PtdIns(3,4)P2 we could not detect a genotype-dependent difference in serum taurine or hypotaurine levels. One explanation could be that the excess taurine generated in the liver is partially utilized to conjugate the excess bile acids produced in Shp−/− mice.[7, 8] Because murine bile

acids are primarily taurine conjugated,[42] we would not expect a substantial alteration in the ratio of taurine:glycine-conjugation of bile acids in Shp−/− mice. In other words, while the fraction of tauro-conjugated bile acids did not differ between WT and Shp−/− mice, the overall concentration of serum tauro-conjugated bile acids was elevated in Shp−/− mice because of the increased total bile acid re-circulating pool in these mice (Fig. 4f). It is also possible that additional homeostatic mechanism such as CSAD substrate availability and altered urinary excretion act to modulate any changes in taurine concentrations that could occur in Shp−/− mice. These data suggest the need for further studies of amino acid homeostasis under conditions where bile acid metabolism is perturbed.