organic solute transporter α-β, Ostα-Ostβ, is essential for intestinal bile acid transport and homeostasis

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 105; no. 10; pp. 3891 - 3896
• Main Authors: Rao, Anuradha, Haywood, Jamie, Craddock, Ann L, Belinsky, Martin G, Kruh, Gary D, Dawson, Paul A
• Format: Journal Article
• Language: English
• Published: National Academy of Sciences 11.03.2008; National Acad Sciences
• Subjects: Bile acids; Biological Sciences; Cholesterols; Excretion; Female animals; Gene expression regulation; Liver; Male animals; Messenger RNA; Mice; Small intestine
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0712328105

The apical sodium-dependent bile acid transporter (Asbt) is responsible for transport across the intestinal brush border membrane; however, the carrier(s) responsible for basolateral bile acid export into the portal circulation remains to be determined. Although the heteromeric organic solute transporter Ostα-Ostβ exhibits many properties predicted for a candidate intestinal basolateral bile acid transporter, the in vivo functions of Ostα-Ostβ have not been investigated. To determine the role of Ostα-Ostβ in intestinal bile acid absorption, the Ostα gene was disrupted by homologous recombination in mice. Ostα⁻/⁻ mice were physically indistinguishable from wild-type mice. In everted gut sac experiments, transileal transport of taurocholate was reduced by >80% in Ostα⁻/⁻ vs. wild-type mice; the residual taurocholate transport was further reduced to near-background levels in gut sacs prepared from Ostα⁻/⁻Mrp3⁻/⁻ mice. The bile acid pool size was significantly reduced (>65%) in Ostα⁻/⁻ mice, but fecal bile acid excretion was not elevated. The decreased pool size in Ostα⁻/⁻ mice resulted from reduced hepatic Cyp7a1 expression that was inversely correlated with ileal expression of fibroblast growth factor 15 (FGF15). These data indicate that Ostα-Ostβ is essential for intestinal bile acid transport in mice. Unlike a block in intestinal apical bile acid uptake, genetic ablation of basolateral bile acid export disrupts the classical homeostatic control of hepatic bile acid biosynthesis.