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Molecular and Cellular Biology, August 2006, p. 6139-6148, Vol. 26, No. 16
0270-7306/06/$08.00+0     doi:10.1128/MCB.00627-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Lysosomal Phospholipase A2 and Phospholipidosis{dagger}

Miki Hiraoka,1,{ddagger} Akira Abe,1,{ddagger} Ye Lu,1 Kui Yang,2 Xianlin Han,2 Richard W. Gross,2 and James A. Shayman1*

Nephrology Division, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan,1 Department of Medicine, Washington University, St. Louis, Missouri2

Received 11 April 2006/ Returned for modification 17 May 2006/ Accepted 27 May 2006

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.

* Corresponding author. Mailing address: Department of Internal Medicine, University of Michigan, Room 1560 MSRB II, 1150 West Medical Center Dr., Ann Arbor, MI 48103-0676. Phone: (734) 763-0992. Fax: (734) 763-0982. E-mail: jshayman{at}umich.edu.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

{ddagger} These authors contributed equally to this work.

Molecular and Cellular Biology, August 2006, p. 6139-6148, Vol. 26, No. 16
0270-7306/06/$08.00+0     doi:10.1128/MCB.00627-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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