Deletion of the transmembrane transporter ABCG1 results in progressive pulmonary lipidosis
Deletion of the transmembrane transporter ABCG1 results in progressive pulmonary lipidosis
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DOI：
10.1074/jbc.m606597200
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发表时间：
2006-09-29
影响因子：
4.8
通讯作者：
Edwards, Peter A.
中科院分区：
文献类型：
--
作者：
Baldan, Angel;Tarr, Paul;Edwards, Peter A.
我们发现，缺乏ATP结合盒跨膜转运蛋白ABCG 1的小鼠表现出进行性和年龄依赖性的严重肺动脉硬化症，概括了人类和小鼠不同呼吸系统综合征的表型。> 6个月大的Abcg 1（-/-）小鼠的肺部表现出广泛的胸膜下细胞积聚、巨噬细胞和肺细胞2型肥大、巨噬细胞和肺细胞中的大量脂质沉积以及表面活性剂水平增加。在3个月龄时未观察到此类异常。然而，基因表达谱显示，在3个月和8个月大的Abcg 1（-/-）小鼠中，编码脂质代谢关键基因的mRNA水平发生了显着变化。这些数据表明，年轻的Abcg 1（-/-）小鼠的肺通过抑制脂质生物合成途径来维持正常的脂质水平，并且随着小鼠的成熟，这种补偿是不充分的。使用A-549细胞（2型肺细胞的模型）的研究表明，ABCG 1的过表达通过依赖于磷脂分泌的过程特异性地刺激细胞胆固醇的流出。此外，我们证明，Abcg 1（-/-），而不是野生型巨噬细胞，积累胆固醇酯液滴与表面活性剂孵育时。总之，这些数据提供了一种机制来解释Abcg 1（-/-）小鼠肺中的脂质蓄积。总之，我们的研究结果表明，ABCG 1在肺脂质稳态中起着重要作用。
We show that mice lacking the ATP-binding cassette transmembrane transporter ABCG1 show progressive and age-dependent severe pulmonary lipidosis that recapitulates the phenotypes of different respiratory syndromes in both humans and mice. The lungs of chow-fed Abcg1(-/-) mice, > 6-months old, exhibit extensive subpleural cellular accumulation, macrophage, and pneumocyte type 2 hypertrophy, massive lipid deposition in both macrophages and pneumocytes and increased levels of surfactant. No such abnormalities are observed at 3 months of age. However, gene expression profiling reveals significant changes in the levels of mRNAs encoding key genes involved in lipid metabolism in both 3- and 8- month-old Abcg1(-/-) mice. These data suggest that the lungs of young Abcg1(-/-) mice maintain normal lipid levels by repressing lipid biosynthetic pathways and that such compensation is inadequate as the mice mature. Studies with A-549 cells, a model for pneumocytes type 2, demonstrate that overexpression of ABCG1 specifically stimulates the efflux of cellular cholesterol by a process that is dependent upon phospholipid secretion. In addition, we demonstrate that Abcg1(-/-), but not wild-type macrophages, accumulate cholesterol ester droplets when incubated with surfactant. Together, these data provide a mechanism to explain the lipid accumulation in the lungs of Abcg1(-/-) mice. In summary, our results demonstrate that ABCG1 plays essential roles in pulmonary lipid homeostasis.