1B-D). Morphometric analysis of cytokeratin 19 staining of liver sections demonstrated less, but not statistically significant (P = 0.06), bile duct proliferation in Ostα−/− BDL mice (Fig. 1E,F). Consistent with this protective effect, hepatic bile acid concentrations were significantly less in BDL Ostα−/− mice (Fig. 2A). Surprisingly, urinary bile acid concentrations were significantly increased as compared to Ostα+/+ BDL mice (Fig. 2D). The biliary and renal parenchymal bile acid levels were unchanged (Fig. 2B,E). However, bilirubin levels were increased by about five-fold in the bile and find more decreased

in the renal parenchyma when compared to Ostα+/+ mice after BDL (Fig. 2C,F). Additional bile collection studies

in untreated Ostα+/+ and Ostα−/− mice revealed that bile flow and bile acid excretion were slightly lower in the Ostα-deficient mice, but bile acid, cholesterol, and phospholipid concentrations were not significantly different over a 90-minute collection period (Supporting Fig. 2). Mass spectrometric analysis of the liver tissue revealed no difference in the bile acid composition between sham-operated Ostα+/+ and Ostα−/− mice (Fig. 3A). However, after http://www.selleckchem.com/Wnt.html BDL there was a 35-fold increase in tetrahydroxy bile acids in the Ostα+/+ liver tissue that was not seen in the Ostα−/− mice (Fig. 3A). Spectrometric analysis of the urine revealed significant accumulation of tetrahydroxylated bile acids (∼40%) and some pentahydroxylated bile acids (∼3.5%) and glucuronides (2.75%) in the Ostα+/+ BDL mice. In contrast, the Ostα−/− BDL mouse urine had limited tetrahydroxylated bile acids (∼10%) and no pentahydroxylated bile acids or glucuronides. Interestingly, the Ostα−/− mouse livers showed a significantly greater accumulation of bile alcohol sulfates than in the Ostα+/+ mice after BDL (Fig. 3B). Similarly, Ostα−/− BDL mice had 4.5 times more urinary excretion of sulfated bile alcohols than Ostα+/+ BDL mice (Table 1). The difference in hepatic and urine bile acid composition may be due to less bile acid accumulation in Ostα−/− mice because of the lower starting bile acid pool, as well as greater hepatic and urine bile

acid clearance. We next determined whether there was a difference in the adaptive response of genes for several nuclear receptors not and for bile acid uptake, synthesis, detoxification, and secretion. In contrast to the wild-type BDL mice, mRNA levels for the nuclear receptors Fxr and Pxr were unchanged after BDL in the Ostα−/− mice (Fig. 4A). However, Car mRNA levels, which were unchanged in the wild-type mice after BDL, were significantly higher in both the sham-operated and BDL Ostα−/− mice (Fig. 4A). In addition, the Ostα−/− BDL mice had significantly higher mRNA levels for Cyp7a1, Cyp2b10, Cyp3a11, sulfotransferase 2a1 (Sult2a1), and uridine diphosphate glucuronosyltransferase 1a1 (Ugt1a1), compared to Ostα+/+ BDL mice (Fig. 4B).