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Papers In Press, published online ahead of print March 1, 2007
J. Lipid Res., doi:10.1194/jlr.M600449-JLR200

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Journal of Lipid Research, Vol. 48, 621-632, March 2007
Copyright © 2007 by American Society for Biochemistry and Molecular Biology

ABCA3 inactivation in mice causes respiratory failure, loss of pulmonary surfactant, and depletion of lung phosphatidylglycerol

Michael L. Fitzgerald^*,, Ramnik Xavier, Kathleen J. Haley, Ruth Welti^**, Julie L. Goss^*, Cari E. Brown^*,, Debbie Z. Zhuang^*,, Susan A. Bell^*, Naifang Lu, Mary Mckee, Brian Seed and Mason W. Freeman^1,*,

^* Lipid Metabolism Unit, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114
Center for Computational and Integrative Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114
Program in Membrane Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114
Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02364
^** Division of Biology, Kansas State University, Manhattan, KS 66506

The online version of this article (available at http://www.jlr.org) contains three supplemental figures, one video and one table.

Published, JLR Papers in Press, December 1, 2006.

¹ To whom correspondence should be addressed. e-mail: freeman{at}molbio.mgh.harvard.edu

The highly branched mammalian lung relies on surfactant, a mixture of phospholipids, cholesterol, and hydrophobic proteins, to reduce intraalveolar surface tension and prevent lung collapse. Human mutations in the ABCA3 transporter have been associated with childhood respiratory disease of variable severity and onset. Here, we report the generation of Abca3 null mice, which became lethargic and cyanotic and died within 1 h of birth. Tissue blots found ABCA3 expression was highest in lung but was also detectable in other tissues, including the kidney. Gross development of kidney and lung was normal in neonatal Abca3^–/– pups, but the mice failed to inflate their lungs, leading to death from atelectatic respiratory failure. Ultrastructural analysis of the Abca3^–/– lungs revealed an absence of surfactant from the alveolar space and a profound loss of mature lamellar bodies, the intracellular storage organelle for surfactant. Mass spectrometry measurement of >300 phospholipids in lung tissue taken from Abca3^–/– mice showed a dramatic reduction of phosphatidylglycerol (PG) levels as well as selective reductions in phosphatidylcholine species containing short acyl chains. These results establish a requirement of ABCA3 for lamellar body formation and pulmonary surfactant secretion and suggest a unique and critical role for the transporter in the metabolism of pulmonary PG. They also demonstrate the utility of the Abca3 null mouse as a model for a devastating human disease.

Supplementary key words ATP cassette binding transporter A1 • lipid transporter • lamellar body

Abbreviations: apoA-I, apolipoprotein A-I; BAC, bacterial artificial chromosome; PC, phosphatidylcholine; PE, phosphatidylethanolamine; PG, phosphatidylglycerol; PI, phosphatidylinositol; PS, phosphatidylserine; SM, sphingomyelin

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