The role of phospholipids in bile formation: what can we learn from animals and human disease?

Abstract

T HAS BEEN recognized in recent years that the hepatocyte is equipped with a set of canalicular ATPBinding Cassette (ABC) transporters, that are specialized in the concentrative transport of compounds from liver into bile. Bile salts, organic anions, organic cations and neutral amphipaths are all pumped into the primary bile via such primary active transporters. The process of phospholipid and cholesterol secretion is complex because it is thought to involve the secretion of bile salts and the subsequent bile salt-mediated solubilization of lipids from the canalicular membrane (1). A key step in lipid secretion is the translocation of phospholipid molecules in the membrane, which is mediated by a member of the above-mentioned family of ABC transporters, namely Mdr2 P-glycoprotein. This was demonstrated by the absence of phospholipid secretion in bile of mice with a disrupted Mdr2 gene (Mdr2-/- mice) (2) and by subsequent demonstration that phospholipids can be translocated (flipped) by this protein from the inner to the outer leaflet of the plasma membrane (3-5). The recognition of Mdr2 P-glycoprotein as a phospholipid flippase has dramatically changed our concepts of biliary lipid secretion. The mechanism of biliary cholesterol secretion in the mouse is secondary to biliary phospholipid secretion. Mdr2-/- mice do not secrete cholesterol into bile. Increasing the hydrophobicity of the bile salt pool in these animals by feeding a cholate-supplemented diet, or infusion of taurocholate or taurodeoxycholate, elicits a partial restoration of cholesterol secretion in the absence of phospholipids (6). This suggests that cholesterol can be extracted from the canalicular membrane, but that under normal conditions this process is strongly impaired due to the absence of phospholipids, which enhance the cholesterol solubility in micelles. Indeed, heterozygous Mdr2+/- mice as well as trans