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Review
. 2014:2014:954781.
doi: 10.1155/2014/954781. Epub 2014 Jul 15.

Molecular mechanisms for biliary phospholipid and drug efflux mediated by ABCB4 and bile salts

Shin-ya Morita  1 , Tomohiro Terada  1
Affiliations
Review

Molecular mechanisms for biliary phospholipid and drug efflux mediated by ABCB4 and bile salts

Shin-ya Morita et al. Biomed Res Int. 2014.

Abstract

On the canalicular membranes of hepatocytes, several ABC transporters are responsible for the secretion of bile lipids. Among them, ABCB4, also called MDR3, is essential for the secretion of phospholipids from hepatocytes into bile. The biliary phospholipids are associated with bile salts and cholesterol in mixed micelles, thereby reducing the detergent activity and cytotoxicity of bile salts and preventing cholesterol crystallization. Mutations in the ABCB4 gene result in progressive familial intrahepatic cholestasis type 3, intrahepatic cholestasis of pregnancy, low-phospholipid-associated cholelithiasis, primary biliary cirrhosis, and cholangiocarcinoma. In vivo and cell culture studies have demonstrated that the secretion of biliary phospholipids depends on both ABCB4 expression and bile salts. In the presence of bile salts, ABCB4 located in nonraft membranes mediates the efflux of phospholipids, preferentially phosphatidylcholine. Despite high homology with ABCB1, ABCB4 expression cannot confer multidrug resistance. This review summarizes our current understanding of ABCB4 functions and physiological relevance, and discusses the molecular mechanism for the ABCB4-mediated efflux of phospholipids.

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Figures

Figure 1
Figure 1
Schematic model of ABCB4. ABCB4 consists of twelve TMHs spanning the plasma membrane and two cytosolic NBFs containing the Walker A, Walker B, and signature motifs. N and C indicate the N- and C-termini of ABCB4, respectively. TMHs are predicted from the crystal structure of mouse Abcb1a (PDB code 3G61) reported by Aller et al. [60]. The residues N91 and N97 are N-glycosylated with complex oligosaccharides. The residues T34, T44, and S49 are phosphorylation sites. The T34M, R47G, K435M, and K1075M mutations impair the phospholipid efflux activity of ABCB4. The G68H, S320F, D459H, I541F, and A953D mutations result in the intracellular retention of ABCB4.
Figure 2
Figure 2
Amino acid sequence alignment of human ABCB1 and ABCB4. Identical amino acids are red. Functional domains are shown above the sequence alignment. TMHs are predicted from the crystal structure of mouse Abcb1a (PDB code 3G61) reported by Aller et al. [60].
Figure 3
Figure 3
Formation of mixed micelles of bile salts, phospholipids, and cholesterol in bile canaliculus. ABCB11 mediates the efflux of bile salts into bile. The bile salt monomers are essential for the phospholipid efflux mediated by ABCB4. In the presence of mixed bile salt/phospholipid micelles, ABCG5/ABCG8 heterodimer mediates the efflux of cholesterol.
Figure 4
Figure 4
Phospholipid substrates for ABCB4. (a) C6-NBD-PC, (b) PC, (c) PE, and (d) SM.
Figure 5
Figure 5
Inhibitors of ABCB4: (a) cyclosporine A, (b) valspodar, (c) verapamil, (d) vinblastine, (e) paclitaxel, and (f) itraconazole.
Figure 6
Figure 6
Model of molecular mechanism of ABCB4-mediated transport. (I) A substrate, mainly PC, enters the binding pocket of ABCB4 from the inner leaflet through the gaps between TMHs. (II) Binding and/or hydrolysis of ATP trigger a conformational change opening the binding pocket to the outer leaflet and the extracellular space. (II-A) In the absence of bile salts, a PC molecule laterally diffuses from the binding pocket of ABCB4 to the outer leaflet through the gaps between TMHs, which represents a floppase function of ABCB4. (II-B) In the presence of bile salts, a PC molecule is taken up from the binding pocket of ABCB4 by bile salt monomers, which represents an exporter function of ABCB4, and then a mixed bile salt/PC micelle is formed in the extracellular space. (II-C) A substrate with sufficient aqueous solubility directly diffuses from the binding pocket into the extracellular space regardless of the presence or absence of bile salts. (III) After dissociation of the substrate and ADP molecules, ABCB4 reset to the inward-facing state.
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