Lysosomal phospholipase A2 and phospholipidosis
Lysosomal phospholipase A2 and phospholipidosis
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DOI：
10.1128/mcb.00627-06
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发表时间：
2006-08-01
影响因子：
5.3
通讯作者：
Shayman, James A.
中科院分区：
文献类型：
--
作者：
Hiraoka, Miki;Abe, Akira;Shayman, James A.
最近对溶酶体磷脂酶 A2（LPLA2）进行了表征，并显示其对磷脂酰胆碱和磷脂酰乙醇胺具有底物特异性。 LPLA2 普遍表达，但在肺泡巨噬细胞中表达最高。采用双重条件基因打靶来阐明 LPLA2 的功能。 LPLA2 缺陷小鼠 (Lpla2(-/-)) 是通过系统性删除 Lpla2 基因的外显子 5 产生的，该基因编码对磷脂酶 A2 活性至关重要的脂肪酶基序。 Lpla2(-/-)小鼠的存活率正常。 Lpla2(-/-) 小鼠交配产仔数正常，表明基因缺陷不会损害生育力或繁殖力。来自野生型小鼠的肺泡巨噬细胞很容易降解放射性标记的磷脂酰胆碱，但 Lpla2(-/-) 小鼠则不然。在 Lpla2(-/-) 小鼠的肺泡巨噬细胞、腹膜巨噬细胞和脾脏中发现磷脂显着积累，特别是磷脂酰乙醇胺和磷脂酰胆碱。到一岁时，Lpla2(-/-) 小鼠表现出明显的脾肿大和肺表面活性物质磷脂水平升高。 Lpla2(-/-) 小鼠肺泡和腹膜巨噬细胞的超微结构检查显示出现具有层状包涵体的泡沫细胞，这是细胞磷脂沉积的标志。因此，溶酶体磷脂酶 A2 的缺乏会导致小鼠泡沫细胞形成、表面活性剂脂质积累、脾肿大和磷脂沉积。
A lysosomal phospholipase A2, LPLA2, was recently characterized and shown to have substrate specificity for phosphatidylcholine and phosphatidylethanolamine. LPLA2 is ubiquitously expressed but is most highly expressed in alveolar macrophages. Double conditional gene targeting was employed to elucidate the function of LPLA2. LPLA2-deficient mice (Lpla2(-/-)) were generated by the systemic deletion of exon 5 of the Lpla2 gene, which encodes the lipase motif essential for the phospholipase A2 activity. The survival of the Lpla2(-/-) mice was normal. Lpla2(-/-) mouse mating pairs yielded normal litter sizes, indicating that the gene deficiency did not impair fertility or fecundity. Alveolar macrophages from wild-type but not Lpla2(-/-) mice readily degraded radiolabeled phosphatidylcholine. A marked accumulation of phospholipids, in particular phosphatidylethanolamine and phosphatidylcholine, was found in the alveolar macrophages, the peritoneal macrophages, and the spleens of Lpla2(-/-) mice. By 1 year of age, Lpla2(-/-) mice demonstrated marked splenomegaly and increased lung surfactant phospholipid levels. Ultrastructural examination of Lpla2(-/-) mouse alveolar and peritoneal macrophages revealed the appearance of foam cells with lamellar inclusion bodies, a hallmark of cellular phospholipidosis. Thus, a deficiency of lysosomal phospholipase A2 results in foam cell formation, surfactant lipid accumulation, splenomegaly, and phospholipidosis in mice.