Changes in cholangiocyte bile salt transporter regulation in mouse orthotopic liver transplantation and the role of bile salts

Background Bile salts cycle between cholangiocytes and hepatocytes through a cholehepatic shunt pathway. The role of bile salt absorption and excretion through cholangiocytes in the development of bile duct injury after orthotopic liver transplantation (OLT) is unknown. We therefore analyzed changes in cholangiocyte bile salt transporter expression in relation to bile composition and biliary injury in a mouse model of OLT. Methods Livers from wild-type mice or mice heterozygous for disruption of the multidrug resistance 2 gene (Mdr2+/-) were transplanted into wild-type recipients. Mdr2+/- mice have normal liver histology and function under normal conditions, but secrete only 50% of the normal amount of phospholipids into their bile, leading to an abnormally high bile salt/ phospholipid ratio. This has been associated with excessive bile duct injury after OLT. Expression of cholangiocyte bile salt transporters Asbt, Ostalpha/ beta was assessed by western blotting and RT-PCR. Levels were correlated with the biliary bile salt/phospholipid ratio and hepatic expression of TNF-alpha and IL1- beta mRNA. Results At baseline, Asbt and Ost-beta protein expression were significantly increased in Mdr2+/- livers, compared to wild-type livers. Transplantation of wild-type livers did not result in significant changes in transporter expression. Transplantation of Mdr2+/- livers, however, resulted in down-regulation of mRNA expression for Asbt, Ostbeta and Ost-alpha after OLT. While levels of Asbt and Ost-alpha mRNA correlated significantly with the biliary bile salt/phospholipid ratio, there was a strong negative correlation between Ost-alpha/beta mRNA expression and the expression of TNFalpha and IL1-beta. Conclusions Asbt expression is regulated in direct proportion to the biliary bile salt/phospholipid ratio. Unbalanced reduction of Asbt and Ost-alpha/ beta expression after OLT may result in bile salt retention in cholangiocytes, which may result in cytotoxicity and aggravate bile duct injury.nrpages: 18status: publishe