Bile acid coenzyme A (CoA):amino-acid N-acyltransferase (BAT) mRNA abundance was reduced in GW4064 treated mice (0.55 ± 0.10, P = 0.031), while bile acid CoA synthetase (BACS) mRNA abundance was not significantly changed with GW4064 treatment (0.86 ± 0.14, P = 0.61) (Fig. 3b). In addition, we found no difference in CSAD mRNA abundance in kidney between control and GW4064 treated mice Deforolimus solubility dmso (1.05 ± 0.12) (Fig. 3c). Previous data have implicated the nuclear receptor SHP in the regulation of CYP7A1 and CYP8B1 expression.[6-8] We found

CYP7A1 and CYP8B1 mRNA expression was increased in Shp−/− mice (5.90 ± 0.86, P = 0.0002, 2.23 ± 0.20, P = 0.0003, respectively, Fig. 4a). We also found that hepatic CSAD mRNA expression was increased in Shp−/− mice (8.49 ± 0.25, P < 0.0001, Fig. 4a), with no difference in hepatic CDO (Fig. 4a), BAT or BACS mRNA levels (0.96 ± 0.01, P = 0.33, and 0.91 ± 0.08, P = 0.45, respectively) (Fig. 4b). In addition, renal CSAD mRNA abundance was not altered (0.95 ± 0.11, P = 0.76) in Shp−/− mice (Fig. 4c). To explore the biochemical significance of the elevated levels of CSAD mRNA we measured hypotaurine concentrations, the immediate product of CSAD activity. We observed a 2.3-fold elevation in hepatic hypotaurine concentration in Shp−/− mice compared to WT controls (WT 46.4 nmol/g vs Shp−/− 108.5 nmol/g, P = 0.034) (Fig. 4d). However, we did not observe changes in either hepatic

(Fig. 4d) or serum (data not shown) taurine content in Shp−/− mice. The bile acid pool composition of Shp−/− mice has been I-BET-762 solubility dmso previously investigated and includes primarily an increase in cholate[7, 22] as well as a shift in the α-muricholate versus β-muricholate fraction.[22] Measurement of taurine conjugates in liver and serum revealed no difference in the fraction of bile acids that were taurine conjugated (Fig. 4e). However, 上海皓元医药股份有限公司 we observed increased concentrations of tauro-conjugated bile acids in serum (Fig. 4f)

but not in liver (data not shown). Fibroblast growth factor 15/19 is produced by ileal enterocytes and acts in the liver via FGF4 receptor (FGF4R)/β-klotho to regulate expression of the CYP7A1 gene[25, 26] Hepatic CYP7A1 and CYP8B1 mRNA levels were suppressed in FGF19-treated mice (0.06 ± 0.03, P = 0.0001, 0.50 ± 0.13, P = 0.005) compared to vehicle-injected control mice (Fig. 5a). By contrast, hepatic CSAD mRNA abundance was not altered by FGF19 treatment (1.03 ± 0.35, P = 0.94). In addition, CDO mRNA abundance in liver and CSAD mRNA abundance in kidney were no different in FGF19-treated mice (1.14 ± 0.12, P = 0.34, 0.98 ± 0.08, P = 0.25, respectively) (Fig. 5a,b). Excess cholesterol and/or oxysterols in the liver act via the nuclear receptor LXRα to increase CYP7A1 mRNA transcription, resulting in accelerated catabolism of cholesterol to bile acids.[27, 28] C57BL/6 mice were gavaged with T-0901317 (a synthetic LXR agonist) for 7 days.