THE ROLE OF PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR-GAMMA IN SURFACTANT CATABOLISM IN THE ALVEOLAR MACROPHAGE

ECU Author/Contributor (non-ECU co-authors, if there are any, appear on document)

Anna DeLane Baker (Creator)

Institution

East Carolina University (ECU )

Web Site: http://www.ecu.edu/lib/

Abstract: Pulmonary alveolar proteinosis (PAP) is a lung disease characterized by surfactant accumulation in the alveolar spaces and alveolar macrophages. Although PAP is rare, surfactant abnormalities occur in many lung diseases including acute respiratory distress syndrome, sarcoidosis, and asthma. Studies have shown that surfactant accumulation in PAP patients results from insufficient catabolism by alveolar macrophages. Research in PAP patients and granulocyte-macrophage colony-stimulating factor knockout (GM-CSF KO) mice revealed deficiencies in the transcription factor peroxisome proliferator-activated receptor-gamma (PPARγ) and downstream cholesterol transporter ATP-binding cassette G1 (ABCG1). PPARγ regulates lipid metabolism in macrophages and is a prominent target of research in the fields of atherosclerosis and diabetes.    This study tested the hypothesis that PPARγ promotes catabolism of surfactant in alveolar macrophages through the transcriptional regulation of ABCG1. Alveolar macrophages from macrophage-specific PPARγ knockout (PPARγ KO) mice accumulate surfactant and exhibit reduced expression of ABCG1 and reduced ABCG1-mediated cholesterol efflux. These results directly link PPARγ-deficiency to surfactant accumulation and demonstrate that PPARγ regulates cholesterol efflux in alveolar macrophages. We next investigated the expression of genes involved in the uptake and biosynthesis of cholesterol in PPARγ KO alveolar macrophages. Expression of key cholesterol biosynthesis genes was suppressed, and cholesterol influx genes (scavenger receptors) were up-regulated. These results suggested PPARγ regulates cholesterol metabolism in alveolar macrophages.    We next investigated the up-regulation of PPARγ in the GM-CSF KO alveolar macrophages by instilling mice with a Lentivirus vector containing PPARγ (Lenti-PPARγ). Reconstitution of PPARγ promoted ABCG1 expression and ABCG1-mediated cholesterol efflux in the alveolar macrophages of GM-CSF KO instilled with Lenti-PPARγ.    Taken together, these observations support the hypothesis that PPARγ-mediated transcriptional regulation of ABCG1 is critical to cholesterol metabolism and the maintenance of surfactant homeostasis overall. Understanding the role of PPARγ in normal surfactant homeostasis provides insight into the pathophysiology of PAP and identifies a potential therapeutic target.  

Additional Information

Publication

Dissertation

Language: English

Date: 2009

Keywords

Biology, Molecular, Biology, General

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