The bile salt export pump: clinical and experimental aspects of genetic and acquired cholestatic liver disease

Abstract

The primary transporter responsible for bile salt secretion is the bile salt export pump (BSEP, ABCB11), a member of the ATP-binding cassette (ABC) superfamily, which is located at the bile canalicular apical domain of hepatocytes. In humans, BSEP deficiency results in several different genetic forms of cholestasis, which include progressive familial intrahepatic cholestasis type 2 (PFIC2), benign recurrent intrahepatic cholestasis type 2 (BRIC2), as well as other acquired forms of cholestasis such as drug-induced cholestasis (DIC) and intrahepatic cholestasis of pregnancy (ICP). Because bile salts play a pivotal role in a wide range of physiologic and pathophysiologic processes, regulation of BSEP expression has been a subject of intense research. The authors briefly describe the molecular characteristics of BSEP and then summarize what is known about its role in the pathogenesis of genetic and acquired cholestatic disorders, emphasizing experimental observations from animal models and cell culture in vitro systems.

Figure 1

Topology of bile salt export pump (BSEP) with 12 transmembrane domains (TMD) and two nucleotide binding domains (NBDs). The nucleotide-binding domains contains Walker A and B as well as a conserved signature C motif of ATP-binding cassette (ABC) superfamily of proteins. BSEP contains N-glycosylation sites (tree) on the first extracellular loop. The “linker” domain lies between the two homologous halves of the protein. A selective number of mutations have been studied and discussed in this review. progressive familial intrahepatic cholestasis type 2 (PFIC2) mutations (x), benign recurrent intrahepatic cholestasis type 2 (BRIC2; star), and intrahepatic cholestasis of pregnancy (ICP; diamond). Two single nucleotide polymorphisms (SNPs; V444A and M677V, cross) are also represented and have been characterized by functional studies (gray star).

Figure 2

Trafficking routes and molecular components involved in the exocytic and endocytic retrieval of bile salt export pump (BSEP). After biosynthesis in the endoplasmic reticulum (ER) and further posttranslational modifications in Golgi, BSEP is indirectly targeted first to a subapical endosomal compartment and then cycles to and from the canalicular membrane. This apical recycling pool is associated with Rab11a endosomes and exocytosis requires myosin light chain, Rab11a, and myosin Vb. BSEP resides within caveolin-containing microdomains along with MDR2 and MRP2 where they function to determine the formation of bile. BSEP endocytosis requires the clathrin-endocytic machinery that includes Hax-1, cortactin, EPS15, and other actin-binding proteins. Many components required for exocytosis and endocytosis are not yet identified.