Elferink R P, Tytgat G N, Groen A K
Department of Gastrointestinal and Liver Diseases, Academic Medical Center, Amsterdam, The Netherlands.
FASEB J. 1997 Jan;11(1):19-28. doi: 10.1096/fasebj.11.1.9034162.
The small apical (canalicular) domains of hepatocytes form a luminal meshwork of tubules between adjacent hepatocytes and are the sites of primary bile formation. Organic compounds are transported across this membrane domain against high concentration gradients. It has been recognized in recent years that the hepatocyte is harnessed with a set of canalicular ATP-dependent transport proteins, specialized in this uphill transport. Bile salts, organic anions, cations, and neutral amphipaths are all pumped into the bile via such primary active transporters. Functionally, these transporters resemble ABC transporters overexpressed in cells with the multidrug resistance phenotype. Indeed, those transporters that have been characterized at the molecular level turn out to be new, or already recognized, members of this family. Phospholipid secretion across the canalicular membrane of the mouse is also mediated by a member of this family, mdr2 P-glycoprotein. This was demonstrated by the absence of phospholipid secretion into bile of mice 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 understanding the mechanism of biliary lipid secretion.
肝细胞的小顶侧（胆小管）结构域在相邻肝细胞之间形成管腔状的网状结构，是初级胆汁形成的部位。有机化合物逆着高浓度梯度跨膜转运通过这一膜结构域。近年来已经认识到，肝细胞配备有一组依赖于ATP的胆小管转运蛋白，专门负责这种上坡转运。胆汁盐、有机阴离子、阳离子和中性两亲分子均通过这种原发性主动转运蛋白泵入胆汁中。在功能上，这些转运蛋白类似于在具有多药耐药表型的细胞中过表达的ABC转运蛋白。实际上，那些在分子水平上已被鉴定的转运蛋白原来是这个家族的新成员或已被认可的成员。小鼠胆小管膜上的磷脂分泌也由该家族的一个成员——多药耐药蛋白2（mdr2）P-糖蛋白介导。这一点通过mdr2基因缺失的小鼠胆汁中缺乏磷脂分泌以及随后在过表达该蛋白的细胞中证明磷脂转运得以证实。将mdr2 P-糖蛋白识别为磷脂翻转酶为P-糖蛋白的功能提供了新的线索，并且是理解胆汁脂质分泌机制的重要一步。
