Ostα-Ostβ is required for bile acid and conjugated steroid disposition in the intestine, kidney, and liver

Mice deficient in the organic solute transporter (Ost)-alpha subunit of the heteromeric organic solute and steroid transporter, Ost alpha- Ost beta, were generated and were found to be viable and fertile but exhibited small intestinal hypertrophy and growth retardation. Bile acid pool size and serum levels were decreased by more than 60% in Ost alpha(-/-) mice, whereas fecal bile acid excretion was unchanged, suggesting a defect in intestinal bile acid absorption. In support of this hypothesis, when [H-3] taurocholic acid or [ 3H] estrone 3-sulfate were administered into the ileal lumen, absorption was lower in Ost alpha(-/-) mice. Interestingly, serum cholesterol and triglyceride levels were also similar to 15% lower in Ost alpha(-/-) mice, an effect that may be related to the impaired intestinal bile acid absorption. After intraperitoneal administration of [H-3] estrone 3-sulfate or [H-3] dehydroepiandrosterone sulfate, Ost alpha(-/-) mice had higher levels of radioactivity in their liver and urinary bladder and less in the duodenum, indicating altered hepatic, renal, and intestinal disposition. Loss of Ost alpha was associated with compensatory changes in the expression of several genes involved in bile acid homeostasis, including an increase in the multidrug resistance-associated protein 3, (Mrp3)/Abcc3, an alternate basolateral bile acid export pump, and a decrease in cholesterol 7 alpha- hydroxylase, Cyp7a1, the rate-limiting enzyme in bile acid synthesis. The latter finding may be explained by increased ileal expression of fibroblast growth factor 15 ( Fgf15), a negative regulator of hepatic Cyp7a1 transcription. Overall, these findings provide direct support for the hypothesis that Ost alpha- Ost beta is a major basolateral transporter of bile acids and conjugated steroids in the intestine, kidney, and liver.