Tytgat Institute for Liver and Intestinal Research, Amsterdam, The Netherlands.
Expert Opin Ther Targets. 2011 Oct;15(10):1173-82. doi: 10.1517/14728222.2011.607163. Epub 2011 Jul 30.
Multidrug resistance 3 (MDR3) P-glycoprotein is a lipid floppase that is encoded by the ATP-binding cassette sub-family B member 4 (ABCB4) gene and plays a crucial role in proper bile formation by transporting phosphatidylcholine across the canalicular plasma membrane of the hepatocyte into bile. The relevance of this function is underscored by the severe pathology that develops in patients with ABCB4 deficiency. This deficiency leads to the destruction of hepatocytes and cholangiocytes by bile salts, because their cytolytic action is not reduced by formation of mixed micelles with phospholipid.
Evidence that phospholipid secretion into bile is also essential for biliary cholesterol secretion as cholesterol dissolves much better in mixed micelles of bile salts and phospholipid than in pure bile salt micelles. As a consequence, net biliary cholesterol secretion depends on the amount of phospholipid secreted and hence, the expression of ABCB4 indirectly determines biliary cholesterol output.
It can be argued that upregulation of the ABCB4 gene expression may not only be beneficial for liver pathology in patients with partial ABCB4 deficiency, but also for the prevention of gallstone formation and optimal cholesterol disposition in a much larger population.
多药耐药蛋白 3（MDR3）P-糖蛋白是一种脂质翻转酶，由 ATP 结合盒亚家族 B 成员 4（ABCB4）基因编码，通过将磷脂酰胆碱跨胆小管质膜转运到胆汁中，在适当的胆汁形成中发挥关键作用。ABCB4 缺乏症患者出现的严重病理情况突出了这种功能的重要性。这种缺乏导致肝细胞和胆管细胞被胆汁盐破坏，因为它们的细胞溶解作用不会因与磷脂形成混合胶束而降低。
有证据表明磷脂分泌到胆汁中对于胆汁胆固醇分泌也是必不可少的，因为胆固醇在胆汁盐和磷脂的混合胶束中比在纯胆汁盐胶束中溶解得更好。因此，净胆汁胆固醇分泌取决于分泌的磷脂量，因此，ABCB4 的表达间接决定了胆汁胆固醇的输出。
可以说，上调 ABCB4 基因表达不仅对部分 ABCB4 缺乏症患者的肝病理有益，而且对预防胆结石形成和更大人群中胆固醇的最佳处置也有益。
