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LIVER AND BILIARY TRACT

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

Department of Environmental Medicine University of Rochester School of Medicine, Rochester, New York

Submitted 2 May 2008 ; accepted in final form 19 May 2008

Mice deficient in the organic solute transporter (Ost)- subunit of the heteromeric organic solute and steroid transporter, Ost-Ostβ, 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–/– mice, whereas fecal bile acid excretion was unchanged, suggesting a defect in intestinal bile acid absorption. In support of this hypothesis, when [³H]taurocholic acid or [³H]estrone 3-sulfate were administered into the ileal lumen, absorption was lower in Ost–/– mice. Interestingly, serum cholesterol and triglyceride levels were also 15% lower in Ost–/– mice, an effect that may be related to the impaired intestinal bile acid absorption. After intraperitoneal administration of [³H]estrone 3-sulfate or [³H]dehydroepiandrosterone sulfate, Ost–/– 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 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-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-Ostβ is a major basolateral transporter of bile acids and conjugated steroids in the intestine, kidney, and liver.

Ost–/– mouse; bile acid absorption; Fxr; Cyp7a1; cholesterol

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