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Ost , Is Essential for Intestinal Bile Acid Transport and Homeostasis

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Ost , Is Essential for Intestinal Bile Acid Transport and Homeostasis The organic solute transporter ␣-␤, Ost␣-Ost␤, is essential for intestinal bile acid transport and homeostasis Anuradha Rao*, Jamie Haywood*, Ann L. Craddock*, Martin G. Belinsky†, Gary D. Kruh‡, and Paul A. Dawson*§ *Department of Internal Medicine, Section on Gastroenterology, Wake Forest University School of Medicine, Medical Center Boulevard, Winston–Salem, NC 27157; †Medical Science Division, Fox Chase Cancer Center, Philadelphia, PA 19111; and ‡Department of Medicine, Section of Hematology/Oncology, University of Illinois, Chicago, IL 60612 Communicated by David W. Russell, University of Texas Southwestern Medical Center, Dallas, TX, December 28, 2007 (received for review November 28, 2007) The apical sodium-dependent bile acid transporter (Asbt) is respon- Ost␣-Ost␤ efficiently transports the major species of bile acids sible for transport across the intestinal brush border membrane; when expressed in transfected cells (3, 4); and (iv) expression of however, the carrier(s) responsible for basolateral bile acid export Ost␣ and Ost␤ mRNA is positively regulated via the bile into the portal circulation remains to be determined. Although the acid-activated nuclear receptor farnesoid X receptor (FXR) heteromeric organic solute transporter Ost␣-Ost␤ exhibits many (6–9), thereby providing a mechanism to ensure efficient export properties predicted for a candidate intestinal basolateral bile acid of bile acids and protection against their cytotoxic accumulation. transporter, the in vivo functions of Ost␣-Ost␤ have not been Although these data are consistent with a role in bile acid investigated. To determine the role of Ost␣-Ost␤ in intestinal bile transport, the in vivo functions of Ost␣-Ost␤ have not been acid absorption, the Ost␣ gene was disrupted by homologous investigated. To elucidate the in vivo role of Ost␣-Ost␤ in recombination in mice. Ost␣؊/؊ mice were physically indistinguish- intestinal bile acid absorption, we produced and characterized able from wild-type mice. In everted gut sac experiments, transileal mice with a disruption in Ost␣. .transport of taurocholate was reduced by >80% in Ost␣؊/؊ vs wild-type mice; the residual taurocholate transport was further Results reduced to near-background levels in gut sacs prepared from Inactivation of Ost␣ in Mice. A targeting construct was designed to ␣Ost␣؊/؊Mrp3؊/؊ mice. The bile acid pool size was significantly replace the proximal promoter and exons 1 and 2 of mouse Ost reduced (>65%) in Ost␣؊/؊ mice, but fecal bile acid excretion was with a neomycin resistance gene by homologous recombination not elevated. The decreased pool size in Ost␣؊/؊ mice resulted (Fig. 1A). Disruption of Ost␣ was confirmed by Southern Ϫ Ϫ from reduced hepatic Cyp7a1 expression that was inversely cor- blotting [supporting information (SI) Fig. 7B]. In Ost␣ / mice, related with ileal expression of fibroblast growth factor 15 (FGF15). Ost␣ mRNA was not detected by real-time PCR (Fig. 1B), and These data indicate that Ost␣-Ost␤ is essential for intestinal bile full-length or alternatively spliced Ost␣ transcripts were not acid transport in mice. Unlike a block in intestinal apical bile acid detected by Northern blot hybridization of intestinal RNA (SI uptake, genetic ablation of basolateral bile acid export disrupts the Fig. 8A). As predicted from the loss of mRNA expression, Ost␣ Ϫ Ϫ classical homeostatic control of hepatic bile acid biosynthesis. protein was not detected in Ost␣ / mice (SI Fig. 8B). Because Ost␣-Ost␤ functions as an obligate heterodimer (3, 10), and their cholesterol ͉ liver disease ͉ mouse model ͉ nuclear receptor relative expression levels appear to be coordinately regulated (6, 7, 9, 11), expression of the Ost␤ subunit was also examined. Although Ost␣ mRNA expression was decreased to undetect- ile acids are synthesized in the liver, secreted into bile, and ␤ delivered to the small intestine, where they act to facilitate able levels, Ost mRNA remained highly expressed (Fig. 1C). B ␤ MEDICAL SCIENCES absorption of fats and fat-soluble vitamins. Intestinal bile acids We next explored whether unpartnered Ost protein would ␣Ϫ/Ϫ ␤ are efficiently absorbed by the terminal ileum and exported into accumulate in Ost mice. Remarkably, Ost protein was ␣Ϫ/Ϫ the portal circulation for return to the liver and resecretion into almost undetectable in Ost mice (Fig. 1D; SI Fig. 8B). As quantified by densitometry, the expression of Ost␤ protein was bile (1). Many of the transporters that function to maintain the Ͼ enterohepatic circulation of bile acids have been identified, decreased by 95% in small intestine, kidney, cecum, and colon. including the Na-taurocholate cotransporting polypeptide ؊/؊ ␣Ϫ/Ϫ␣ (Ntcp; Slc10a1) and bile salt export pump (Bsep; Abcb11), which Phenotype of Ost Mice. Ost mice are viable and fertile; mediate hepatocytic uptake and export, respectively, and apical crosses between heterozygous mice produced the predicted Mendelian distribution of wild-type and mutant genotypes. sodium-dependent bile acid transporter (Asbt) (Slc10a2), which Ost␣Ϫ/Ϫ mice were indistinguishable from Ost␣ϩ/Ϫ or wild-type mediates uptake across the apical brush border member in ileum littermates in terms of survival and gross appearance, with the (2). Notably absent from this list is the intestinal basolateral exception of a small growth deficit observed in Ost␣Ϫ/Ϫ pups (SI transporter responsible for bile acid export from enterocytes into Fig. 9). In addition, adult male Ost␣Ϫ/Ϫ mice (3 months of age) portal blood, and this represents an important missing link in our had significantly longer small intestines than wild-type mice understanding of the enterohepatic circulation. Recently, the (male mice: Ost␣ϩ/ϩ, 41.2 Ϯ 1.3 cm vs. Ost␣Ϫ/Ϫ, 47.7 Ϯ 1.7 cm; heteromeric transporter Ost␣-Ost␤ was identified as a candidate ileal basolateral bile acid transporter by using a transcriptional profiling approach (3). There is abundant evidence supporting a Author contributions: A.R. and P.A.D. designed research; A.R., J.H., A.L.C., and P.A.D. role for Ost␣-Ost␤ in intestinal basolateral bile acid transport, performed research; M.G.B. and G.D.K. contributed new reagents/analytic tools; A.R. and including: (i) Ost␣ and Ost␤ are highly expressed in ileum, and P.A.D. analyzed data; and A.R., G.D.K., and P.A.D. wrote the paper. their expression closely parallels that of the Asbt (3, 4); (ii) The authors declare no conflict of interest. expression of mouse Ost␣-Ost␤ protein, which is composed of §To whom correspondence should be addressed. E-mail: [email protected]. two subunits, a 352-aa polytopic membrane protein (Ost␣) and This article contains supporting information online at www.pnas.org/cgi/content/full/ a 154-aa type I membrane protein (Ost␤) (5), is largely restricted 0712328105/DC1. to the lateral and basal membranes of ileal enterocytes (3); (iii) © 2008 by The National Academy of Sciences of the USA www.pnas.org͞cgi͞doi͞10.1073͞pnas.0712328105 PNAS ͉ March 11, 2008 ͉ vol. 105 ͉ no. 10 ͉ 3891–3896 Downloaded by guest on September 30, 2021 Fig. 1. Knockout of mouse Ost␣.(A) Schematic showing the strategy used to delete Ost␣.(B) Quantitation of Ost␣ mRNA expression (Seg 1-5, small intestinal segments 1–5; Pr. Col., proximal colon; Dis. Col., distal colon). (C) Quantitation of Ost␤ mRNA expression. Pooled aliquots of RNA (n ϭ 5) prepared from individual mice of the indicated genders and genotypes were analyzed by real-time PCR. (D) Analysis of Ost␤ protein expression in male wild-type and Ost␣Ϫ/Ϫ mice. (Upper) Protein extracts were prepared from small intestinal segments of individual mice (n ϭ 5), pooled, and aliquots (50 ␮g) were subjected to immunoblotting analysis. (Lower) Pooled aliquots (n ϭ 5) of protein extracts from ileum (10 ␮g) or from kidney (K), cecum (Ce), and proximal colon (Pc) (50 ␮g) were subjected to immunoblotting analysis. The blots were probed sequentially by using antibodies to Ost␤ and ␤-actin. n ϭ 9–11; P ϭ 0.0057) (female mice: Ost␣ϩ/ϩ, 40.3 Ϯ 1.6 cm vs. similar to Ost␣Ϫ/Ϫ mice with regard to survival, gross appear- Ost␣Ϫ/Ϫ, 44.7 Ϯ 2.0 cm; n ϭ 7; P Ͼ 0.05), and Ost␣Ϫ/Ϫ mice ance, and growth (data not shown). exhibited small intestinal hypertrophy. This small intestinal phenotype was not observed in AsbtϪ/Ϫ or Mrp3Ϫ/Ϫ mice. No Intestinal Bile Acid Transport. Everted gut sac preparations of intestinal inflammation or diarrhea was observed in Ost␣Ϫ/Ϫ Wilson and Wiseman (12) were used to investigate the contri- ␣ ␤ mice maintained on a chow diet. Plasma parameters were bution of Ost -Ost and other transporters to intestinal bile acid measured at 3 months of age and did not differ significantly transport. In agreement with previous studies using everted gut Ϫ Ϫ sacs (13) or in situ perfused small intestine (14), the mucosal- between wild-type and Ost␣ / mice, with the exception of lower ␣Ϫ/Ϫ to-serosal transport of taurocholate (TC) in wild-type mice was plasma cholesterol and triglyceride levels in female Ost mice largely restricted to distal small intestine (SI Fig. 10A); ileal TC (SI Table 1). Because the organic anion transporter Mrp3 has transport was Ͼ20-fold higher in ileal vs. proximal segments of been proposed to participate in intestinal basolateral bile acid Ϫ Ϫ Ϫ Ϫ small intestine (Fig. 2; SI Fig. 10A). Hence, the contribution of transport, a limited number of Ost␣ / Mrp3 / mice were also transporters known or hypothesized to be involved in intestinal ϩ Ϫ ϩ Ϫ generated. Crossing heterozygous (Ost␣ / Mrp3 / ) mice pro- bile acid absorption was examined by using everted jejunal duced the predicted Mendelian distribution of wild-type and (segment 2) or ileal (segment 4) sacs prepared from the follow- mutant genotypes; Ost␣Ϫ/ϪMrp3Ϫ/Ϫ mice exhibit a phenotype ing genotypes: Ost␣ϩ/ϩ and Ost␣Ϫ/Ϫ littermates, Ost␣ϩ/ϩ Fig.
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