J. Lipid Res.
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A more recent version of this article appeared on December 1, 2007

Papers In Press, published online ahead of print September 11, 2007
J. Lipid Res., doi:10.1194/jlr.P700022-JLR200
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Submitted on June 18, 2007
Revised on July 30, 2007
Accepted on September 10, 2007

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

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

Internal Medicine, East Carolina University, Greenville, NC 27834

Corresponding Author: thomassenm{at}ecu.edu

Patients with pulmonary alveolar proteinosis (PAP) display impaired surfactant clearance, foamy, lipid-filled alveolar macrophages, and elevated 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 knock-out (KO) mice which exhibit PAP-like pulmonary pathology and elevated pulmonary cholesterol. Alveolar macrophages from both sources displayed a striking similarity in transporter gene dysregulation consisting of deficient ABCG1 accompanied by highly elevated ABCA1. Peroxisome proliferator-activated receptor gamma (PPARgamma), a known regulator of both transporters, was deficient as previously reported. In contrast, the liver-X-receptor (LXR)alpha, which also upregulates both transporters, was highly elevated. 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 elevated ABCG1 expression. Results suggest that ABCG1 deficiency in PAP and GM-CSF KO alveolar macrophages is due to 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.


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