Enterohepatic bile salt transporters in normal physiology and liver disease  Gerd A. Kullak-ublick, Bruno Stieger, Peter J. Meier  Gastroenterology  Volume 126, Issue 1, Pages 322-342 (January 2004) DOI: 10.1053/j.gastro.2003.06.005

Figure 1 Bile salt transporters in human liver and intestine. At the basolateral hepatocyte membrane, the major uptake system for conjugated bile salts is the Na+-dependent bile salt transporter NTCP (SLC10A1). Na+-independent bile salt uptake is mediated by the multispecific organic anion transporting polypeptides OATP-A (SLC21A3), OATP-C (SLC21A6), and to a minor extent OATP8 (SLC21A8). At the canalicular hepatocyte membrane, excretion of monovalent bile salts is mediated by the bile salt export pump BSEP (ABCB11), whereas excretion of nonbile salt organic anions such as bilirubin glucuronides, as well as of divalent sulfated or glucuronidated bile salts, is mediated by the multidrug resistance associated protein MRP2 (ABCC2). Biliary excretion of phospholipids and cholesterol is mediated by MDR3 (ABCB4) and ABCG5/ABCG8, respectively. The FIC1 gene product, which may be involved in bile salt transport, is also expressed at the canalicular membrane of hepatocytes. MRP3 (ABCC3) is a basolateral efflux system for anionic conjugates that also mediates low-affinity transport of monovalent bile salts. MRP3 is expressed in hepatocytes, cholangiocytes, and enterocytes. MRP4 (ABCC4) is a basolateral efflux system for anionic conjugates including sulfated bile salts, and its mouse homolog (Mrp4) is induced in the livers of Fxr-/- mice that exhibit elevated concentrations of bile salts.226 In cholangiocytes and enterocytes, the apical Na+-dependent bile salt transporter ASBT (SLC10A2) mediates bile salt uptake across the luminal membrane. Basolateral efflux into the periductular capillary plexus occurs via organic anion exchange mechanisms and via MRP3. Ductular bile is modified by chloride channels such as the cystic fibrosis transmembrane conductance regulator (CFTR) and the chloride/bicarbonate exchanger (anion exchanger 2, AE2). Enterocytes also express MRP2, the cholesterol transporter ABCG5/ABCG8, and the PXR-inducible xenobiotic efflux pump MDR1 at their apical membrane. Open symbols denote Na+-cotransport (NTCP, ASBT) or anion exchange mechanisms; grey symbols represent ATP-binding cassette (ABC) transporters. Gastroenterology 2004 126, 322-342DOI: (10.1053/j.gastro.2003.06.005)