Significance of Biliary Phospholipids for Maintenance of the Gastrointestinal Mucosal Barrier and Hepatocellular Integrity

Flavio Nervi:

Biliary phosphatidylcholines (PLs) exhibit a very specific, relatively hydrophilic fatty acid composition and account for .95% of total biliary phospholipids.

 They represent essential amphiphilic bile constituents that increase the capacity for cholesterol solubilization and transport, by promoting formation of polymolecular aggregates, including lamellar vesicles and bile salt mixed micelles.1,2 Secretion of biliary PLs is coupled to cholesterol as unilamellar vesicles from the canalicular membrane through the mdr2 P-glycoprotein. The mdr2 P-glycoprotein is a phospholipid flippase,3,4 one of the numerous ABC canalicular transporters that normally function as adenosine triphosphate (ATP)-dependent export pumps.5 Some members of this family of transporters are critical to endobiotic and xenobiotic secretion into bile, including many commonly used nonsteroidal antiinflammatory drugs (NSAIDs) that undergo enterohepatic circulation, e.g., indomethacin and sulindac.6 PL secretion into the canaliculi depends primarily on three factors: turnover and hydrophobicity of the bile acid pool,1,2 level of gene expression, and activity of the relevant canalicular P-glycoprotein (MDR3 in humans and mdr2 in mice). For nearly 3 decades, enhancing micellar solubilization and transport of biliary cholesterol have been the primary metabolic and physiological functions attributed to biliary PLs.1 However, more recent studies in the mdr2 knockout mice provide compelling evidence that biliary PLs actually play an important role in hepatic cytoprotection3 and in fat absorption and chylomicron production.7 Pioneering in vitro studies by Coleman’s group in isolated cell systems8,9 raised the possibility that biliary PLs and cholesterol play an important physiological role in protecting cell integrity and function against the toxic detergent effects of bile acid simple micelles.