Disruption of Abcg5 and Abcg8 in mice reveals their crucial role in biliary cholesterol secretion
Disruption of Abcg5 and Abcg8 in mice reveals their crucial role in biliary cholesterol secretion
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DOI：
10.1073/pnas.252582399
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发表时间：
2002-12-10
影响因子：
11.1
通讯作者：
Hobbs, HH
中科院分区：
文献类型：
--
作者：
Yu, LQ;Hammer, RE;Hobbs, HH
胆固醇和其他固醇主要通过分泌到胆汁中排出体外。在谷甾醇血症患者中，两种ATP结合盒（ABC）半转运蛋白ABCG 5或ABCG 8中的任一种突变导致胆汁中固醇分泌减少，这一过程涉及这些转运蛋白。为了阐明ABCG 5和ABCG 8在固醇运输中的作用，我们在小鼠（G5 G8（-/-））中破坏了Abcg 5和Abcg 8。G5 G8（-/-）小鼠对膳食植物甾醇的吸收分数增加了2- 3倍，这与血浆谷甾醇增加约30倍有关。与野生型动物相比，G5 G8（-/-）小鼠的胆汁胆固醇浓度极低（平均值= 0.4 vs. 5.5 mumol/ml），并且仅在胆固醇喂养下适度增加。血浆和肝脏胆固醇水平降低了50%，在饲料喂养的G5 G8（-/-）小鼠和增加2.4倍和18倍，分别胆固醇喂养后。这些数据表明，ABCG 5和ABCG 8是胆固醇有效分泌到胆汁中所必需的，并且这些基因的破坏显著增加了血浆和肝脏胆固醇水平对饮食胆固醇含量变化的响应性。
Cholesterol and other sterols exit the body primarily by secretion into bile. In patients with sitosterolemia, mutations in either of two ATP-binding cassette (ABC) half-transporters, ABCG5 or ABCG8, lead to reduced secretion of sterols into bile, implicating these transporters in this process. To elucidate the roles of ABCG5 and ABCG8 in the trafficking of sterols, we disrupted Abcg5 and Abcg8 in mice (G5G8(-/-)). The G5G8(-/-) mice had a 2- to 3-fold increase in the fractional absorption of dietary plant sterols, which was associated with an approximate to30-fold increase in plasma, sitosterol. Biliary cholesterol concentrations were extremely low in the G5G8(-/-) mice when compared with wild-type animals (mean = 0.4 vs. 5.5 mumol/ml) and increased only modestly with cholesterol feeding. Plasma and liver cholesterol levels were reduced by 50% in the chow-fed G5G8(-/-) mice and increased 2.4- and 18-fold, respectively, after cholesterol feeding. These data indicate that ABCG5 and ABCG8 are required for efficient secretion of cholesterol into bile and that disruption of these genes increases dramatically the responsiveness of plasma and hepatic cholesterol levels to changes in dietary cholesterol content.