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

Abstract

Mice deficient in the organic solute transporter (Ost)-α subunit of the heteromeric organic solute and steroid transporter, Ostα-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 Ostα−/− 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 Ostα−/− mice. Interestingly, serum cholesterol and triglyceride levels were also ∼15% lower in Ostα−/− 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, Ostα−/− 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 Ostα 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 7α-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 Ostα-Ostβ is a major basolateral transporter of bile acids and conjugated steroids in the intestine, kidney, and liver.

Bile acid transporters

“…2 ). As predicted from this model, OST ␣ null mice had signifi cantly increased FGF15 expression and reduced hepatic Cyp7a1 expression ( 170,171 ). These fi ndings further supported a central role of FGF15/19 in regulating hepatic bile acid synthesis ( 243,244 ) as recently confi rmed in the liver and intestine-specifi c FXR and LRH-1 null mice and reviewed by the late Dr. Roger Davis ( 75,245,246 ).…”

“…No inherited defects have been reported for the OST ␣ or OST ␤ genes in humans; however, targeted inactivation of the OST ␣ gene in mice resulted in impaired intestinal bile acid absorption and altered bile acid metabolism ( 170,171 ). In contrast to ASBT null mice that exhibited the predicted sequelae associated with intestinal bile acid malabsorption ( 157,242 ), the OST ␣ null mice exhibited a more complex phenotype.…”

“…Recent studies have identifi ed OST ␣ -OST ␤ as a major mechanism responsible for intestinal basolateral membrane bile acid export ( 170,171 ). Although highly expressed in terminal ileum, OST ␣ -OST ␤ is also expressed at lower levels in proximal small intestine of rodents and humans ( 150,151,172 ) where it can serve to export bile acids that were passively absorbed across the apical brush border membrane of the enterocyte.…”

Ostα−/−mice exhibit altered expression of intestinal lipid absorption genes, resistance to age-related weight gain, and modestly improved insulin sensitivity

“…The in vivo functions of the transporter have subsequently been characterized in two Ost␣-deficient (Ost␣ 25). Neonatal Ost␣ Ϫ/Ϫ mice are ϳ25% smaller than wild-type mice, but this difference disappears shortly after weaning (1,25). The mechanism for the growth delay in Ost␣ Ϫ/Ϫ mice is unknown.…”

“…The mechanism for the growth delay in Ost␣ Ϫ/Ϫ mice is unknown. The small intestine is longer and heavier in Ost␣ Ϫ/Ϫ than wild-type mice, with apparent ileal enterocyte dysplasia (1,13,25,32). Ost␣ Ϫ/Ϫ mice exhibit impaired transileal bile acid absorption coupled with an increase in ileal FGF15 production and a decrease in hepatic Cyp7a1 expression resulting from activation of the FXR in the ileocyte (1,12,13,25).…”