Targeted PPARγ deficiency in alveolar macrophages disrupts surfactant catabolism
Targeted PPARγ deficiency in alveolar macrophages disrupts surfactant catabolism
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DOI：
10.1194/jlr.m001651
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发表时间：
2010-06-01
影响因子：
6.5
通讯作者：
Thomassen, Mary Jane
中科院分区：
文献类型：
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作者：
Baker, Anna D.;Malur, Anagha;Thomassen, Mary Jane
表面活性剂在粒状巨噬细胞刺激因子（GMCSF）基因敲除（KO）小鼠和肺肺泡蛋白质病（PAP）患者中积聚在中和肺肺泡蛋白质病（PAP）患者中，导致中和抗GM-CSF的患者中和抗GM-CSF抗体。 PAP患者和GM-CSF KO小鼠的肺泡巨噬细胞缺乏过氧化物酶体增殖物激活的受体伽马（PPARγ）和ATP结合盒（ABC）脂质转运蛋白ABCG1。先前的研究表明，GMCSF诱导了PPAR伽玛。因此，我们假设PPAR伽马通过调节ABCG1促进了表面活性剂分解代谢。为了解决这一假设，利用了巨噬细胞特异性的PPAR伽玛（Macppar Gamma）敲除小鼠。 Macppar Gamma KO小鼠会形成泡沫，脂质的油红O阳性肺泡巨噬细胞。脂质分析显示，Macppar Gamma KO肺泡巨噬细胞和细胞外支气管肺泡灌洗（BAL）衍生的液体的胆固醇和磷脂含量显着增加。 Macppar Gamma KO肺泡巨噬细胞显示ABCG1表达降低，ABCG1介导的胆固醇排出不足。脂质代谢也可以通过肝X受体（LXR）-ABCA1途径来调节。有趣的是，ABCA1和LXRβ表达升高，表明该途径不足以防止肺泡巨噬细胞中的表面活性剂积累。这些结果表明，PPAR伽马通过调节ABCG1.-Baker，A。D.，A。Malur，B。P. Barna，S。Ghosh，M。S. Kavuru，A。G. Malur，A。G. Malur和M. J. Thomassen，从而介导了表面活性剂稳态的关键作用。肺泡巨噬细胞中有针对性的PPARγ缺乏破坏了表面活性剂的分解代谢。 J. Lipid Res。 2010。51：1325-1331。
Surfactant accumulates in alveolar macrophages of granulocyte-macrophage colony-stimulating factor (GMCSF) 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 deficient in peroxisome proliferator-activated receptor-gamma (PPAR gamma) and ATP-binding cassette (ABC) lipid transporter ABCG1. Previous studies have demonstrated that GMCSF induces PPAR gamma. We therefore hypothesized that PPAR gamma promotes surfactant catabolism through regulation of ABCG1. To address this hypothesis, macrophage-specific PPAR gamma (MacPPAR gamma) knockout mice were utilized. MacPPAR gamma KO mice develop foamy, lipid-engorged Oil Red O positive alveolar macrophages. Lipid analyses revealed significant increases in the cholesterol and phospholipid contents of MacPPAR gamma KO alveolar macrophages and extracellular bronchoalveolar lavage (BAL)-derived fluids. MacPPAR gamma 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 LXR beta expression were elevated, indicating that this pathway is not sufficient to prevent surfactant accumulation in alveolar macrophages. These results suggest that PPAR gamma mediates a critical role in surfactant homeostasis through the regulation of ABCG1.-Baker, A. D., A. Malur, B. P. Barna, S. Ghosh, M. S. Kavuru, A. G. Malur, and M. J. Thomassen. Targeted PPAR gamma deficiency in alveolar macrophages disrupts surfactant catabolism. J. Lipid Res. 2010. 51: 1325-1331.