title: Targeted PPAR{gamma} deficiency in alveolar macrophages disrupts surfactant catabolism.
abstract: Surfactant accumulates in alveolar macrophages of granulocyte-macrophage colony-stimulating factor (GM-CSF) knockout (KO) mice and pulmonary alveolar proteinosis (PAP) patients with a functional loss of GM-CSF resulting from neutralizing anti-GM-CSF antibody. Alveolar macrophages from PAP patients and GM-CSF KO mice are de-ficient in peroxisome proliferator-activated receptor-gamma (PPARgamma) and ATP-binding cassette (ABC) lipid transporter ABCG1. Previous studies have demonstrated that GM-CSF induces PPARgamma. We therefore hypothesized that PPARgamma promotes surfactant catabolism through regulation of ABCG1. To address this hypothesis, macrophage-specific PPARgamma (MacPPARgamma) knockout mice were utilized. MacPPARgamma KO mice develop foamy, lipid-engorged Oil Red O positive alveolar macrophages. Lipid analyses revealed significant increases in the cholesterol and phospholipid contents of MacPPARgamma KO alveolar macrophages and extracellular bronchoalveolar lavage (BAL)-derived fluids. MacPPARgamma KO alveolar macrophages showed decreased expression of ABCG1 and a deficiency in ABCG1-mediated cholesterol efflux to HDL. Lipid metabolism may also be regulated by liver X receptor (LXR)-ABCA1 pathways. Interestingly, ABCA1 and LXRbeta expression were elevated, indicating that this pathway is not sufficient to prevent surfactant accumulation in alveolar macrophages. These results suggest that PPARgamma mediates a critical role in surfactant homeostasis through the regulation of ABCG1.
authors.affiliation: Department of Internal Medicine, East Carolina University, Greenville, NC, USA.
authors.forename: Anna D
authors.initials: AD
authors.lastname: Baker
authors.forename: Anagha
authors.initials: A
authors.lastname: Malur
authors.forename: Barbara P
authors.initials: BP
authors.lastname: Barna
authors.forename: Shobha
authors.initials: S
authors.lastname: Ghosh
authors.forename: Mani S
authors.initials: MS
authors.lastname: Kavuru
authors.forename: Achut G
authors.initials: AG
authors.lastname: Malur
authors.forename: Mary Jane
authors.initials: MJ
authors.lastname: Thomassen
mesh_terms: D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D000818:Animals; D002784:Cholesterol / Q000378:metabolism; D055786:Gene Knockout Techniques; D008074:Lipoproteins / Q000378:metabolism; D008075:Lipoproteins, HDL / Q000378:metabolism; D000071518:Liver X Receptors; D008168:Lung / Q000378:metabolism; D016676:Macrophages, Alveolar / Q000378:metabolism*; D051379:Mice; D009928:Organ Specificity; D057093:Orphan Nuclear Receptors / Q000378:metabolism; D047495:PPAR gamma / Q000172:deficiency* / Q000235:genetics*; D013501:Surface-Active Agents / Q000378:metabolism*
chemical_list: C487540:ABCG1 protein, mouse; D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D018528:ATP-Binding Cassette Transporters; D008074:Lipoproteins; D008075:Lipoproteins, HDL; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D047495:PPAR gamma; D013501:Surface-Active Agents; D002784:Cholesterol