Phosphatidylcholine translocator ABCB4

Definition:

[Isoform 1]: Energy-dependent phospholipid efflux translocator that acts as a positive regulator of biliary lipid secretion. Functions as a floppase that translocates specifically phosphatidylcholine (PC) from the inner to the outer leaflet of the canalicular membrane bilayer into the canaliculi of hepatocytes. Translocation of PC makes the biliary phospholipids available for extraction into the canaliculi lumen by bile salt mixed micelles and therefore protects the biliary tree from the detergent activity of bile salts. Plays a role in the recruitment of phosphatidylcholine (PC), phosphatidylethanolamine (PE) and sphingomyelin (SM) molecules to nonraft membranes and to further enrichment of SM and cholesterol in raft membranes in hepatocytes. Required for proper phospholipid bile formation (By similarity). Indirectly involved in cholesterol efflux activity from hepatocytes into the canalicular lumen in the presence of bile salts in an ATP-dependent manner. Promotes biliary phospholipid secretion as canaliculi-containing vesicles from the canalicular plasma membrane. In cooperation with ATP8B1, functions to protect hepatocytes from the deleterious detergent activity of bile salts. Does not confer multidrug resistance (By similarity).

References:

[1]. Jeppe A Olsen, et al. Structure of the human lipid exporter ABCB4 in a lipid environment. Nat Struct Mol Biol. 2020 Jan;27(1):62-70. [Content Brief]

[2]. Julien Gautherot, et al. Phosphorylation of ABCB4 impacts its function: insights from disease-causing mutations. Hepatology. 2014 Aug;60(2):610-21. [Content Brief]

[3]. Shin-ya Morita, et al. Bile salt-stimulated phospholipid efflux mediated by ABCB4 localized in nonraft membranes. J Lipid Res. 2013 May;54(5):1221-30. [Content Brief]

[4]. Shin-ya Morita, et al. Bile salt-dependent efflux of cellular phospholipids mediated by ATP binding cassette protein B4. Hepatology. 2007 Jul;46(1):188-99. [Content Brief]

[5]. Edward J Andress, et al. Molecular mechanistic explanation for the spectrum of cholestatic disease caused by the S320F variant of ABCB4. Hepatology. 2014 May;59(5):1921-31. [Content Brief]

[6]. Annemiek Groen, et al. Complementary functions of the flippase ATP8B1 and the floppase ABCB4 in maintaining canalicular membrane integrity. Gastroenterology. 2011 Nov;141(5):1927-37.e1-4. [Content Brief]

[7]. A van Helvoort, et al. MDR1 P-glycoprotein is a lipid translocase of broad specificity, while MDR3 P-glycoprotein specifically translocates phosphatidylcholine. Cell. 1996 Nov 1;87(3):507-17. [Content Brief]

[8]. A J Smith, et al. The human MDR3 P-glycoprotein promotes translocation of phosphatidylcholine through the plasma membrane of fibroblasts from transgenic mice. FEBS Lett. 1994 Nov 14;354(3):263-6. [Content Brief]

[9]. Dario Degiorgio, et al. Two ABCB4 point mutations of strategic NBD-motifs do not prevent protein targeting to the plasma membrane but promote MDR3 dysfunction. Eur J Hum Genet. 2014 May;22(5):633-9. [Content Brief]

[10]. Raquel Gordo-Gilart, et al. Functional analysis of ABCB4 mutations relates clinical outcomes of progressive familial intrahepatic cholestasis type 3 to the degree of MDR3 floppase activity. Gut. 2015 Jan;64(1):147-55. [Content Brief]

[11]. A R Crawford, et al. Hepatic secretion of phospholipid vesicles in the mouse critically depends on mdr2 or MDR3 P-glycoprotein expression. Visualization by electron microscopy. J Clin Invest. 1997 Nov 15;100(10):2562-7. [Content Brief]

[12]. Jean-Louis Delaunay, et al. Functional defect of variants in the adenosine triphosphate-binding sites of ABCB4 and their rescue by the cystic fibrosis transmembrane conductance regulator potentiator, ivacaftor (VX-770). Hepatology. 2017 Feb;65(2):560-570. [Content Brief]

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