UDCA to partially block the transmembrane apical Na

This article is available online at http://www.jlr.org UDCA to partially block the transmembrane apical Na + dependent bile acid transporter ( 7 ). Thus far, no intracellular receptor for UDCA has been reported. The farnesoid X receptor  (FXR ) is a nuclear receptor that binds to and is activated by bile acids ( 8–10 ). FXR forms heterodimers with the retinoid X receptor  (RXR ) and regulates the expression of target genes involved in bile acid homeostasis as well as lipid and glucose metabolism ( 11 ). Chenodeoxycholic acid (CDCA) is the best natural ligand of FXR ( 8–10 ). However, deoxycholic acid (DCA), the bile acid most frequently associated with cholestatic diseases and colorectal cancer, also binds to FXR ( 8, 9 ). Given the association of FXR with the processes underlying cholestatic diseases ( 12 ), liver cancer ( 13, 14 ), and colorectal cancer ( 15–17 ), it would seem to be a likely molecular target for UDCA. However, confl icting reports exist regarding UDCA’s ability to bind and activate FXR ( 8–10, 18 ). Ileal bile acid binding protein (IBABP) is a small cytoplasmic protein mainly expressed in ileal epithelium. Although initially categorized as a member of the fatty acid binding protein family ( 19 ), IBABP binds exclusively to bile acids ( 20 ). The bile acid selectivity arises from the fact that IBABP has a larger binding pocket than other members of the fatty acid binding protein family ( 21, 22 ). The precise biological function of IBABP is not clear, but it is presumed to coordinate with the apical bile acid transporter in the uptake of bile acids into ileocytes. IBABP also associates with FXR ( 23 ) and could potentially help mediate the transcriptional response to bile acids. IBABP binds two bile acids in a cooperative manner ( 21, 24 ). The basis of cooperative binding is the formation of a hydrogen bond between the 3-OH of the bile acid occupying site 1, and either the 7-OH or 12-OH of Abstract Ursodeoxycholic acid (UDCA, ursodiol) is used to prevent damage to the liver in patients with primary biliary cirrhosis. The drug also prevents the progression of colorectal cancer and the recurrence of high-grade colonic dysplasia. However, the molecular mechanism by which UDCA elicits its benefi cial effects is not entirely understood. The aim of this study was to determine whether ileal bile acid binding protein (IBABP) has a role in mediating the effects of UDCA. We fi nd that UDCA binds to a single site on IBABP and increases the affi nity for major human bile acids at a second binding site. As UDCA occupies one of the bile acid binding sites on IBABP, it reduces the cooperative binding that is often observed for the major human bile acids. Furthermore, IBABP is necessary for the full activation of farnesoid X receptor  (FXR ) by bile acids, including UDCA. These observations suggest that IBABP may have a role in mediating some of the intestinal effects of UDCA. — Fang, C., F. V. Filipp, and J. W. Smith. Unusual binding of ursodeoxycholic acid to ileal bile acid binding protein: role in activation of FXR . J. Lipid Res. 2012. 53: 664–673.