THE ROLE OF MDR2 P-GLYCOPROTEIN IN HEPATOBILIARY LIPID TRANSPORT

The small apical (canalicular) domains of hepatocytes form a luminal m eshwork of tubules between adjacent hepatocytes and are the sites of p rimary bile formation, Organic compounds are transported across this m embrane domain against high concentration gradients, It has been recog nized hi recent years that the hepatocyte is harnessed,vith a set of c analicular ATP-dependent transport proteins, specialized in this uphil l transport, Bile salts, organic anions, cations, and neutral amphipat hs are all pumped into the bile via such primary active transporters, Functionally, these transporters resemble ABC transporters overexpress ed in cells with the multidrug resistance phenotype. Indeed, those tra nsporters that have been characterized at the molecular level turn out to be new, or already recognized, members of this family, Phospholipi d secretion across the canalicular membrane of the mouse is also media ted by a member of this family, mdr2 P-glycoprotein. This was demonstr ated by the absence of phospholipid. secretion into bile of slice with a disrupted mdr2 gene and by subsequent demonstration of phospholipid translocation in cells that overexpress this protein, The recognition of mdr2 P-glycoprotein as a phospholipid flippase sheds new Light on the function of P-glycoproteins and is an important step in understand ing the mechanism of biliary Lipid secretion.