Organic solute transporter alpha-beta (Ostalpha-Ostbeta) is a heteromeric
bile acid and
sterol transporter that facilitates the enterohepatic and renal-hepatic circulation of
bile acids. Hepatic expression of this basolateral
membrane protein is increased in
cholestasis, presumably to facilitate removal of toxic
bile acids from the liver. In this study, we show that the cholestatic phenotype induced by common bile duct
ligation (BDL) is reduced in mice genetically deficient in Ostalpha. Although Ostalpha(-/-) mice have a smaller
bile acid pool size, which could explain lower serum and hepatic levels of
bile acids after BDL, gallbladder
bilirubin and urinary
bile acid concentrations were significantly greater in Ostalpha(-/-) BDL mice, suggesting additional alternative adaptive responses. Livers of Ostalpha(-/-) mice had higher
messenger RNA levels of
constitutive androstane receptor (Car) than wild-type BDL mice and increased expression of Phase I
enzymes (Cyp7a1, Cyp2b10, Cyp3a11), Phase II
enzymes (Sult2a1, Ugt1a1), and Phase III transporters (Mrp2, Mrp3). Following BDL, the
bile acid pool size increased in Ostalpha(-/-) mice and
protein levels for the hepatic basolateral membrane export transporters,
multidrug resistance-associated protein 3 (Mrp3) and Mrp4, and for the apical
bilirubin transporter, Mrp2, were all increased. In the kidney of Ostalpha(-/-) mice after BDL, the apical
bile acid uptake transporter Asbt is further reduced, whereas the apical export transporters Mrp2 and Mrp4 are increased, resulting in a significant increase in urinary
bile acid excretion.
CONCLUSION: These findings indicate that loss of Ostalpha provides protection from liver injury in obstructive
cholestasis through adaptive responses in both the kidney and liver that enhance clearance of
bile acids into urine and through detoxification pathways most likely mediated by the
nuclear receptor Car.