| Restoration of PPARγ reverses lipid accumulation in alveolar macrophages of GM-CSF knockout mice. | |
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MedLine Citation:
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PMID: 21036914 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Pulmonary alveolar proteinosis (PAP) is a lung disease characterized by a deficiency of functional granulocyte macrophage colony-stimulating factor (GM-CSF) resulting in surfactant accumulation and lipid-engorged alveolar macrophages. GM-CSF is a positive regulator of PPARγ that is constitutively expressed in healthy alveolar macrophages. We previously reported decreased PPARγ and ATP-binding cassette transporter G1 (ABCG1) levels in alveolar macrophages from PAP patients and GM-CSF knockout (KO) mice, suggesting PPARγ and ABCG1 involvement in surfactant catabolism. Because ABCG1 represents a PPARγ target, we hypothesized that PPARγ restoration would increase ABCG1 and reduce macrophage lipid accumulation. Upregulation of PPARγ was achieved using a lentivirus expression system in vivo. GM-CSF KO mice received intratracheal instillation of lentivirus (lenti)-PPARγ or control lenti-eGFP. Ten days postinstillation, 79% of harvested alveolar macrophages expressed eGFP, demonstrating transduction. Alveolar macrophages showed increased PPARγ and ABCG1 expression after lenti-PPARγ instillation, whereas PPARγ and ABCG1 levels remained unchanged in lenti-eGFP controls. Alveolar macrophages from lenti-PPARγ-treated mice also exhibited reduced intracellular phospholipids and increased cholesterol efflux to HDL, an ABCG1-mediated pathway. In vivo instillation of lenti-PPARγ results in: 1) upregulating ABCG1 and PPARγ expression of GM-CSF KO alveolar macrophages, 2) reducing intracellular lipid accumulation, and 3) increasing cholesterol efflux activity. |
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Authors:
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Anagha Malur; Anna D Baker; Almedia J McCoy; Greg Wells; Barbara P Barna; Mani S Kavuru; Achut G Malur; Mary Jane Thomassen |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2010-10-29 |
Journal Detail:
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Title: American journal of physiology. Lung cellular and molecular physiology Volume: 300 ISSN: 1522-1504 ISO Abbreviation: Am. J. Physiol. Lung Cell Mol. Physiol. Publication Date: 2011 Jan |
Date Detail:
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Created Date: 2010-12-20 Completed Date: 2011-01-28 Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 100901229 Medline TA: Am J Physiol Lung Cell Mol Physiol Country: United States |
Other Details:
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Languages: eng Pagination: L73-80 Citation Subset: IM |
Affiliation:
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East Carolina Univ., Greenville, NC 27834, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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ATP-Binding Cassette Transporters
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genetics,
metabolism Animals Cholesterol / metabolism Granulocyte-Macrophage Colony-Stimulating Factor / deficiency, genetics*, physiology Humans Lipids / physiology Macrophages, Alveolar / metabolism, pathology Mice Mice, Knockout PPAR gamma / genetics*, metabolism, therapeutic use Pulmonary Alveolar Proteinosis / drug therapy, genetics, metabolism Pulmonary Surfactants / metabolism |
| Chemical | |
Reg. No./Substance:
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0/ABCG1 protein, human; 0/ATP-Binding Cassette Transporters; 0/Lipids; 0/PPAR gamma; 0/Pulmonary Surfactants; 57-88-5/Cholesterol; 83869-56-1/Granulocyte-Macrophage Colony-Stimulating Factor |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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