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Journal of Lipid Research, Vol. 48, 2762-2768, December 2007
Copyright © 2007 by American Society for Biochemistry and Molecular Biology

Patient-Oriented and Epidemiological Research

ABCG1 is deficient in alveolar macrophages of GM-CSF knockout mice and patients with pulmonary alveolar proteinosis

Mary Jane Thomassen^1,*, Barbara P. Barna^*, Achut G. Malur, Tracey L. Bonfield, Carol F. Farver^,**, Anagha Malur^*, Heidi Dalrymple^*, Mani S. Kavuru^* and Maria Febbraio

^* Program in Lung Cell Biology and Translational Research, Division of Pulmonary and Critical Care Medicine, East Carolina University, Greenville, NC
Department of Microbiology and Immunology, East Carolina University, Greenville, NC
Department of Pulmonary, Allergy, and Critical Care Medicine, Cleveland Clinic Foundation, Cleveland, OH
^** Department of Anatomic Pathology, Cleveland Clinic Foundation, Cleveland, OH
Department of Cell Biology, Cleveland Clinic Foundation, Cleveland, OH

Published, JLR Papers in Press, September 11, 2007.

¹ To whom correspondence should be addressed. e-mail: thomassenm{at}ecu.edu

ABSTRACT

Patients with pulmonary alveolar proteinosis (PAP) display impaired surfactant clearance, foamy, lipid-filled alveolar macrophages, and increased cholesterol metabolites within the lung. Neutralizing autoantibodies to granulocyte-macrophage colony-stimulating factor (GM-CSF) are also present, resulting in virtual GM-CSF deficiency. We investigated ABCG1 and ABCA1 expression in alveolar macrophages of PAP patients and GM-CSF knockout (KO) mice, which exhibit PAP-like pulmonary pathology and increased pulmonary cholesterol. Alveolar macrophages from both sources displayed a striking similarity in transporter gene dysregulation, consisting of deficient ABCG1 accompanied by highly increased ABCA1. Peroxisome proliferator-activated receptor (PPAR), a known regulator of both transporters, was deficient, as reported previously. In contrast, the liver X receptor , which also upregulates both transporters, was highly increased. GM-CSF treatment increased ABCG1 expression in macrophages in vitro and in PAP patients in vivo. Overexpression of PPAR by lentivirus-PPAR transduction of primary alveolar macrophages, or activation by rosiglitazone, also increased ABCG1 expression. These results suggest that ABCG1 deficiency in PAP and GM-CSF KO alveolar macrophages is attributable to the absence of a GM-CSF-mediated PPAR pathway. These findings document the existence of ABCG1 deficiency in human lung disease and highlight a critical role for ABCG1 in surfactant homeostasis.

Supplementary key words liver X receptor • peroxisome proliferator-activated receptor • ATP binding cassette transporter A1 • ATP binding cassette transporter G1 • foam cells • granulocyte-macrophage colony-stimulating factor

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