Accumulation of dietary cholesterol in sitosterolemia caused by mutations in adjacent ABC transporters
Accumulation of dietary cholesterol in sitosterolemia caused by mutations in adjacent ABC transporters
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DOI：
10.1126/science.290.5497.1771
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发表时间：
2000-12-01
期刊：
影响因子：
56.9
通讯作者：
Hobbs, HH
中科院分区：
文献类型：
--
作者：
Berge, KE;Tian, H;Hobbs, HH
在健康的个体中，胆固醇摄入量的急剧变化会导致血浆胆固醇水平的轻微变化。谷甾醇血症是一种常染色体隐性遗传病，其特征是肠道吸收增加，胆汁中膳食类固醇排泄减少，高胆固醇血症和过早的冠状动脉粥样硬化。我们在9例谷固醇血症患者中发现了两个相邻的、相反定向的基因，它们编码三磷酸腺苷结合盒(ABC)转运体家族的新成员(ABCG8有6个突变，ABCG5有1个突变)。这两个基因在肝脏和肠道中的表达水平最高，在小鼠中，胆固醇喂养上调了这两个基因的表达。这些数据表明，ABCG5和ABCG8正常情况下合作限制肠道吸收和促进胆道排泄类固醇，这些转运体的突变形式易于类固醇积累和动脉粥样硬化。
In healthy individuals, acute changes in cholesterol intake produce modest changes in plasma cholesterol levels. A striking exception occurs in sitosterolemia, an autosomal recessive disorder characterized by increased intestinal absorption and decreased biliary excretion of dietary sterols, hypercholesterolemia, and premature coronary atherosclerosis. We identified seven different mutations in two adjacent, oppositely oriented genes that encode new members of the adenosine triphosphate (ATP)-binding cassette (ABC) transporter family (six mutations in ABCG8 and one in ABCG5) in nine patients with sitosterolemia. The two genes are expressed at highest levels in Liver and intestine and, in mice, cholesterol feeding up-regulates expressions of both genes. These data suggest that ABCG5 and ABCG8 normally cooperate to Limit intestinal absorption and to promote biliary excretion of sterols, and that mutated forms of these transporters predispose to sterol accumulation and atherosclerosis.