title: ABCG1 regulates pulmonary surfactant metabolism in mice and men.
abstract: Idiopathic pulmonary alveolar proteinosis (PAP) is a rare lung disease characterized by accumulation of surfactant. Surfactant synthesis and secretion are restricted to epithelial type 2 (T2) pneumocytes (also called T2 cells). Clearance of surfactant is dependent upon T2 cells and macrophages. ABCG1 is highly expressed in both T2 cells and macrophages. ABCG1-deficient mice accumulate surfactant, lamellar body-loaded T2 cells, lipid-loaded macrophages, B-1 lymphocytes, and immunoglobulins, clearly demonstrating that ABCG1 has a critical role in pulmonary homeostasis. We identify a variant in theABCG1promoter in patients with PAP that results in impaired activation ofABCG1by the liver X receptor α, suggesting that ABCG1 basal expression and/or induction in response to sterol/lipid loading is essential for normal lung function. We generated mice lacking ABCG1 specifically in either T2 cells or macrophages to determine the relative contribution of these cell types on surfactant lipid homeostasis. These results establish a critical role for T2 cell ABCG1 in controlling surfactant and overall lipid homeostasis in the lung and in the pathogenesis of human lung disease.
authors.affiliation: Department of Medicine, University of California Los Angeles, Los Angeles, CA 90095.|Department of Biological Chemistry, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095.|Molecular Biology Institute, University of California Los Angeles, Los Angeles, CA 90095.|Johnson Comprehensive Cancer Center, University of California Los Angeles, Los Angeles, CA 90095.
authors.forename: Thomas Q
authors.initials: TQ
authors.lastname: de Aguiar Vallim
authors.affiliation: Department of Medicine, University of California Los Angeles, Los Angeles, CA 90095.|Division of Pulmonary and Critical Care Medicine, University of California Los Angeles, Los Angeles, CA 90095.
authors.forename: Elinor
authors.initials: E
authors.lastname: Lee
authors.affiliation: Department of Biological Chemistry, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095.
authors.forename: David J
authors.initials: DJ
authors.lastname: Merriott
authors.affiliation: Columbia Nano Initiative Electron Microscopy Facility, Columbia University, New York, NY 10027.
authors.forename: Christopher N
authors.initials: CN
authors.lastname: Goulbourne
authors.affiliation: Department of Biological Chemistry, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095.
authors.forename: Joan
authors.initials: J
authors.lastname: Cheng
authors.affiliation: Department of Biological Chemistry, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095.
authors.forename: Angela
authors.initials: A
authors.lastname: Cheng
authors.affiliation: Department of Medicine, University of California San Diego, La Jolla, CA 92093.
authors.forename: Ayelet
authors.initials: A
authors.lastname: Gonen
authors.affiliation: Edward A. Doisy Department of Biochemistry and Molecular Biology, Saint Louis University, St. Louis, MO 63104.
authors.forename: Ryan M
authors.initials: RM
authors.lastname: Allen
authors.affiliation: Edward A. Doisy Department of Biochemistry and Molecular Biology, Saint Louis University, St. Louis, MO 63104.|Center for Cardiovascular Research, School of Medicine, Saint Louis University, St. Louis, MO 63104.
authors.forename: Elisa N D
authors.initials: END
authors.lastname: Palladino
authors.affiliation: Edward A. Doisy Department of Biochemistry and Molecular Biology, Saint Louis University, St. Louis, MO 63104.|Center for Cardiovascular Research, School of Medicine, Saint Louis University, St. Louis, MO 63104.
authors.forename: David A
authors.initials: DA
authors.lastname: Ford
authors.affiliation: Department of Medicine, University of California Los Angeles, Los Angeles, CA 90095.|Division of Pulmonary and Critical Care Medicine, University of California Los Angeles, Los Angeles, CA 90095.
authors.forename: Tisha
authors.initials: T
authors.lastname: Wang
authors.affiliation: Edward A. Doisy Department of Biochemistry and Molecular Biology, Saint Louis University, St. Louis, MO 63104.
authors.forename: Ángel
authors.initials: Á
authors.lastname: Baldán
authors.affiliation: Department of Medicine, University of California Los Angeles, Los Angeles, CA 90095 etarling@mednet.ucla.edu.|Molecular Biology Institute, University of California Los Angeles, Los Angeles, CA 90095.|Johnson Comprehensive Cancer Center, University of California Los Angeles, Los Angeles, CA 90095.
authors.forename: Elizabeth J
authors.identifier: 0000-0002-0599-0432
authors.initials: EJ
authors.lastname: Tarling
mesh_terms: D000072283:A549 Cells; D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000328:Adult; D056809:Alveolar Epithelial Cells / Q000166:cytology / Q000378:metabolism; D000818:Animals; D002784:Cholesterol / Q000096:biosynthesis / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation; D055786:Gene Knockout Techniques; D006706:Homeostasis; D006801:Humans; D007136:Immunoglobulins / Q000378:metabolism; D008264:Macrophages / Q000166:cytology / Q000378:metabolism; D008297:Male; D051379:Mice; D008875:Middle Aged; D011649:Pulmonary Alveolar Proteinosis / Q000378:metabolism / Q000473:pathology; D011663:Pulmonary Surfactants / Q000378:metabolism*
chemical_list: D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D007136:Immunoglobulins; D011663:Pulmonary Surfactants; D002784:Cholesterol
keywords: ATP binding cassette transporter G1; cholesterol; lung; phospholipid; pulmonary alveolar proteinosis