Abstract
Several ABC transporters of the human liver are responsible for the secretion of bile salts, lipids and cholesterol. Their interplay protects the biliary tree from the harsh detergent activity of bile salts. Among these transporters, ABCB4 is essential for the translocation of phosphatidylcholine (PC) lipids from the inner to the outer leaflet of the canalicular membrane of hepatocytes. ABCB4 deficiency can result in altered PC to bile salt ratios, which led to intrahepatic cholestasis of pregnancy, low phospholipid associated cholelithiasis, drug induced liver injury or even progressive familial intrahepatic cholestasis type 3. Although PC lipids only account for 30–40% of the lipids in the canalicular membrane, 95% of all phospholipids in bile are PC lipids. We discuss this discrepancy in the light of PC synthesis and bile salts favoring certain lipids. Nevertheless, the in vivo extraction of PC lipids from the outer leaflet of the canalicular membrane by bile salts should be considered as a separate step in bile formation. Therefore, methods to characterize disease causing ABCB4 mutations should be considered carefully, but such an analysis represents a crucial point in understanding the currently unknown transport mechanism of this ABC transporter.
Funding source: Deutsche Forschungsgemeinschaft
Award Identifier / Grant number: CRC 974
Funding statement: The authors apologize to all their colleagues whose work was not adequately cited due to space limitations. We thank Jan Stindt, Carola Dröge, Michele Bonus, Holger Gohlke, Verena Keitel, Sander Smits, Manuel Wagner, Marcel Lagedroste and all members of the Institute of Biochemistry for fruitful discussions. This work was supported by the Deutsche Forschungsgemeinschaft (Funder Id 10.13039/501100001659, CRC 974 project B03 to L.S.).
Conflict of interest statement: The authors declare that they have no conflicts of interest with the contents of this article.
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