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J. Biol. Chem., Vol. 281, Issue 39, 29401-29410, September 29, 2006

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Deletion of the Transmembrane Transporter ABCG1 Results in Progressive Pulmonary Lipidosis^*

Ángel Baldán¹, Paul Tarr², Charisse S. Vales, Joy Frank, Thomas K. Shimotake^¶, Sam Hawgood^¶, and Peter A. Edwards^||3

From the Departments of Biological Chemistry, Medicine, and the ^||Molecular Biology Institute at University of California, Los Angeles, California 90095 and the ^¶Cardiovascular Research Institute and Department of Pediatrics, University of California, San Francisco, California 94118

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.

Received for publication, July 11, 2006 , and in revised form, August 1, 2006.

^* This work was supported in part by National Institutes of Health Grants NIH30568 and NIH68445 (to P. A. E.), a grant from the Laubisch Fund (to P. A. E.), and a grant from Pfizer, Inc. (to P. A. E.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Recipient of an American Heart Association (Western Affiliate) Postdoctoral Fellowship (0525010Y).

² Recipient of National Institutes of Health Predoctoral Fellowship NHLBI T32 69766.

³ To whom correspondence should be addressed: Dept. of Biological Chemistry, CHS 33-257, David Geffen School of Medicine at UCLA, 10833 Le Conte Ave., Los Angeles, CA 90095. Tel.: 310-206-3717; Fax: 310-794-7345; E-mail: pedwards{at}mednet.ucla.edu.

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