Berge K E, Tian H, Graf G A, Yu L, Grishin N V, Schultz J, Kwiterovich P, Shan B, Barnes R, Hobbs H H
Department of Molecular Genetics and McDermott Center for Human Growth and Development and Howard Hughes Medical Institute, University of Texas Southwestern Medical Center at Dallas, 5323 Harry Hines Boulevard, Dallas, TX 75390-9046, USA.
Science. 2000 Dec 1;290(5497):1771-5. doi: 10.1126/science.290.5497.1771.
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.
在健康个体中，胆固醇摄入量的急性变化会使血浆胆固醇水平产生适度变化。一个显著的例外是谷甾醇血症，这是一种常染色体隐性疾病，其特征为膳食固醇的肠道吸收增加、胆汁排泄减少、高胆固醇血症以及过早出现冠状动脉粥样硬化。我们在9例谷甾醇血症患者中，于两个相邻、方向相反的基因中鉴定出7种不同的突变，这两个基因编码三磷酸腺苷（ATP）结合盒（ABC）转运蛋白家族的新成员（ABCG8中有6种突变，ABCG5中有1种突变）。这两个基因在肝脏和肠道中表达水平最高，并且在小鼠中，给予胆固醇会上调这两个基因的表达。这些数据表明，ABCG5和ABCG8通常协同作用以限制肠道吸收并促进固醇的胆汁排泄，并且这些转运蛋白的突变形式易导致固醇蓄积和动脉粥样硬化。
