Structural Basis of Bile Acid Transport

Bile acids are synthesized from cholesterol in hepatocytes and secreted through the biliary tract into the small intestine, where they aid in absorption of lipids and fat‐soluble vitamins. Through a process known as enterohepatic recirculation, more than 90% of secreted bile acids are then retrieved from the intestine and returned to the liver for resecretion. In humans, there are two Na + ‐dependent bile acid transporters involved in the enterohepatic recirculation, the Na + ‐ taurocholate co‐transporting polypeptide (NTCP; also known as SLC10A1) expressed in hepatocytes, and the apical sodium‐dependent bile acid transporter (ASBT; also known as SLC10A2) expressed on enterocytes in the terminal ileum. Both NTCP and ASBT utilize the Na + gradient to drive concentrative transport of bile acids. In recent years, ASBT has attracted much interest as a potential drug target for treatment of hypercholesterolemia, because inhibition of ASBT reduces reabsorption of bile acids, thus increasing bile acid synthesis and consequently cholesterol consumption. To understand the structural changes associated with the coupled transport of Na + and bile acids, we solved two structures of an ASBT homologue from Yersinia frederiksenii (ASBT Yf ) in a lipid environment, which reveal that a large rigid‐body rotation of a substrate‐binding domain gives the conserved ‘crossover’ region, where two discontinuous transmembrane helices cross each other, alternating accessibility from either side of the cell membrane. This result has implications for the location and orientation of the bile acid during transport, as well as for the translocation pathway for Na + .