Organic anion–transporting polypeptide 1b2 (Oatp1b2) is important for the hepatic uptake of unconjugated bile acids: Studies in Oatp1b2-null mice

Abstract

The organic anion–transporting polypeptide 1b family (Oatp1b2 in rodents and OATP1B1/1B3 in humans) is liver-specific and transports various chemicals into the liver. However, the role of the Oatp1b family in the hepatic uptake of bile acids (BAs) into the liver is unknown. Therefore, in Oatp1b2-null mice, the concentrations of BAs in plasma, liver, and bile were compared with wild-type (WT) mice. It was first determined that livers of the Oatp1b2-null mice were not compensated by altered expression of other hepatic transporters. However, the messenger RNA of Cyp7a1 was 70% lower in the Oatp1b2-null mice. Increased expression of fibroblast growth factor 15 in intestines of Oatp1b2-null mice might be responsible for decreased hepatic expression of Cyp7a1 in Oatp1b2-null mice. The hepatic concentration and biliary excretion of conjugated and unconjugated BAs were essentially the same in Oatp1b2-null and WT mice. The serum concentration of taurine-conjugated BAs was essentially the same in the two genotypes. In contrast, the serum concentrations of unconjugated BAs were 3–45 times higher in Oatp1b2-null than WT mice. After intravenous administration of cholate to Oatp1b2-null mice, its clearance was 50% lower than in WT mice, but the clearance of taurocholate was similar in the two genotypes. Conclusion This study indicates that Oatp1b2 has a major role in the hepatic uptake of unconjugated BAs.

Intestinal transport and metabolism of bile acids

“…In mice engineered to delete the entire Oatp1a/ 1b locus (encompassing Slco1b2 , Slco1a4 , Slco1a1 , Slco1a6 , and Slco1a5 ), plasma levels of conjugated bile acids were unchanged, whereas unconjugated bile acid levels increased by approximately 13-fold ( 13 ). Similar results were obtained for a mouse model where only the Oatp1b2 ( Slco1b2 ) gene was deleted, indicating that this OATP is primarily responsible for mediating hepatic clearance of unconjugated bile acids in mice ( 50 ). Because unconjugated bile in male but not female mice.…”

The emerging role of transport systems in liver function tests

“…While the cause of the conjugated bilirubin elevation has not been determined, the increase in unconjugated bilirubin supports a role of Oatps in hepatocellular uptake of bilirubin. Mild elevation of mainly conjugated bilirubin is also observed in mice with inactivated Slco1b2 (Zaher et al, 2008), which was recently confirmed (Csanaky et al, 2011). Taken together, these human and animal data strongly support a physiological involvement of hepatocellular OATPs in the hepatic uptake of unconjugated and conjugated bilirubin.…”

Hepatic Mttp deletion reverses gallstone susceptibility in L-Fabp knockout mice

“…We explored the possible mechanisms for altered canalicular cholesterol secretion following LD feeding using RNA profi ling of candidate transporter genes as a fi rst step in identifying the pathways involved. The fi ndings show decreased mRNA abundance of the intracellular cholesterol transporter Abcg1 ( 18 ) in Mttp-LKO and DKO mice and increased abundance of bile acid transporters Abcb11 ( 19 ) and Oatp4 ( 20 ) in DKO mice, but no changes in mRNA expression of the canalicular cholesterol effl ux transporter Abcg5/g8 or of Srb1 ( Fig. 3A ).…”