Langheim Silvia, Yu Liqing, von Bergmann Klaus, Lütjohann Dieter, Xu Fang, Hobbs Helen H, Cohen Jonathan C
Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
J Lipid Res. 2005 Aug;46(8):1732-8. doi: 10.1194/jlr.M500115-JLR200. Epub 2005 Jun 1.
The major pathway for the removal of cholesterol from the body is via secretion into the bile. Three members of the ATP binding cassette (ABC) family, ABCG5 (G5), ABCG8 (G8), and ABCB4 (MDR2), are required for the efficient biliary export of sterols. Here, we examined the interdependence of these three ABC transporters for biliary sterol secretion. Biliary lipid levels in mice expressing no MDR2 (Mdr2-/- mice) were compared with those of Mdr2-/- mice expressing 14 copies of a human G5 (hG5) and hG8 transgene (Mdr2-/-;hG5G8Tg mice). Mdr2-/- mice had only trace amounts of biliary cholesterol and phospholipids. The Mdr2-/-;hG5G8Tg mice had biliary cholesterol levels as low as those of Mdr2-/- mice. Thus, MDR2 expression is required for G5G8-mediated biliary sterol secretion. To determine whether the reduction in fractional absorption of dietary sterols associated with G5G8 overexpression is secondary to the associated increase in biliary cholesterol, we compared the fractional absorption of sterols in Mdr2-/-;hG5G8Tg and hG5G8Tg animals. Inactivation of MDR2 markedly attenuated the reduction in fractional sterol absorption associated with G5G8 overexpression. These results are consistent with the notion that increased biliary cholesterol secretion contributes to the reduction in fractional sterol absorption associated with G5G8 overexpression.
体内胆固醇清除的主要途径是分泌入胆汁。ATP结合盒（ABC）家族的三个成员，ABCG5（G5）、ABCG8（G8）和ABCB4（MDR2），是甾醇有效胆汁排泄所必需的。在此，我们研究了这三种ABC转运蛋白在胆汁甾醇分泌中的相互依赖性。将不表达MDR2的小鼠（Mdr2-/-小鼠）的胆汁脂质水平与表达14个拷贝人G5（hG5）和hG8转基因的Mdr2-/-小鼠（Mdr2-/-;hG5G8Tg小鼠）的胆汁脂质水平进行比较。Mdr2-/-小鼠的胆汁胆固醇和磷脂含量仅为微量。Mdr2-/-;hG5G8Tg小鼠的胆汁胆固醇水平与Mdr2-/-小鼠一样低。因此，MDR2的表达是G5G8介导的胆汁甾醇分泌所必需的。为了确定与G5G8过表达相关的膳食甾醇吸收分数降低是否继发于胆汁胆固醇的相应增加，我们比较了Mdr2-/-;hG5G8Tg和hG5G8Tg动物中甾醇的吸收分数。MDR2的失活显著减弱了与G5G8过表达相关的甾醇吸收分数降低。这些结果与以下观点一致，即胆汁胆固醇分泌增加导致了与G5G8过表达相关的甾醇吸收分数降低。
