Deletion of the ileal basolateral bile acid transporter identifies the cellular sentinels that regulate the bile acid pool.

B ile acids are potent detergents and are essential for efficient digestion and absorption of dietary fat. Bile acids are synthesized by the liver from cholesterol, excreted into bile, and stored in the gallbladder. After ingestion of a fatcontaining diet, the gallbladder contracts, forcing bile to enter the lumen of the proximal duodenum. Lipids in bile acid emulsions are absorbed in the proximal jejunum, whereas the majority of bile acids are absorbed in distal ileum, whereupon they are transported back to the liver through the portal blood. Each cycle of the bile acid enterohepatic circulation pathway is associated with a small ( 5%) loss, which is replaced through de novo hepatic synthesis (1). The same amphipathic properties that allow bile acids to emulsify lipids also make them membrane-disruptive agents (2). Thus, limiting the accumulation of bile acids within cells making up the enterohepatic circulation helps to prevent cytotoxicity. Because bile acids have vastly different structures and abilities to emulsify lipids (2), the composition of the bile acid pool can markedly influence their ability to facilitate lipid digestion and absorption. The itinerary of bile acids involves transport across apical and basolateral surfaces of cells in the liver (hepatocytes) and intestine (enterocytes) (Fig. 1). Identification of the apical ileal sodium-dependent bile acid transporter (Asbt) explained how bile acids are efficiently reabsorbed by the ileal epithelial cell (3). This discovery stimulated the search for a transporter that would efficiently transport bile acids across the basolateral surface membrane of the ileal enterocyte. In a recent issue of PNAS, Rao et al. (4) identify Ost /Ost as the heterodimeric bile acid transporter responsible for the basolateral transport of bile acids out of the ileal epithelial cell. The new insights provided by these studies provide an integrated pathway through which the expression of multiple distinct high-affinity bile acid transporters efficiently retrieves bile acids from the distal ileum and delivers them to the liver. The farnesoid X receptor (FXR) is a member of the nuclear receptor superfamily and, as a heterodimer with RXR, is activated by bile acids. Because FXR induces the expression of Ost and Ost , it seemed plausible that the Ost / heterodimer could be the ileal basolateral bile acid transporter (5). Whereas cell culture studies showed that coexpression of Ost and Ost could enhance the apical-to-basolateral transport of taurocholate, it was not clear that this is the major transporter responsible for basolateral ileal bile acid transport in vivo (6). The studies of Rao et al. (4) clearly show that the expression of Ost is necessary for the heterodimeric complex Ost /Ost to be expressed at the basolateral surface and for the bile acids to be efficiently absorbed in mice. Moreover, using everted gut sacs, Rao et al. show that the transileal transport of taurocholate is reduced by 80% in Ost / mice vs. sacs from wild-type mice. These data clearly establish the Ost / heterodimer as the major transporter responsible for the ileal basolateral transport of bile acids. A parallel story involves the mechanism by which bile acid levels in the