Department of Internal Medicine, Division of Pulmonary, Critical Care, and Sleep Medicine, East Carolina University, Greenville, NC 27834, USA.
Biochem Biophys Res Commun. 2010 Mar 19;393(4):682-7. doi: 10.1016/j.bbrc.2010.02.056. Epub 2010 Feb 17.
Peroxisome proliferator-activated receptor-gamma (PPARgamma) is a nuclear transcription factor involved in lipid metabolism that is constitutively expressed in the alveolar macrophages of healthy individuals. PPARgamma has recently been implicated in the catabolism of surfactant by alveolar macrophages, specifically the cholesterol component of surfactant while the mechanism remains unclear. Studies from other tissue macrophages have shown that PPARgamma regulates cholesterol influx, efflux, and metabolism. PPARgamma promotes cholesterol efflux through the liver X receptor-alpha (LXRalpha) and ATP-binding cassette G1 (ABCG1). We have recently shown that macrophage-specific PPARgamma knockout (PPARgamma KO) mice accumulate cholesterol-laden alveolar macrophages that exhibit decreased expression of LXRalpha and ABCG1 and reduced cholesterol efflux. We hypothesized that in addition to the dysregulation of these cholesterol efflux genes, the expression of genes involved in cholesterol synthesis and influx was also dysregulated and that replacement of PPARgamma would restore regulation of these genes. To investigate this hypothesis, we have utilized a Lentivirus expression system (Lenti-PPARgamma) to restore PPARgamma expression in the alveolar macrophages of PPARgamma KO mice. Our results show that the alveolar macrophages of PPARgamma KO mice have decreased expression of key cholesterol synthesis genes and increased expression of cholesterol receptors CD36 and scavenger receptor A-I (SRA-I). The replacement of PPARgamma (1) induced transcription of LXRalpha and ABCG1; (2) corrected suppressed expression of cholesterol synthesis genes; and (3) enhanced the expression of scavenger receptors CD36. These results suggest that PPARgamma regulates cholesterol metabolism in alveolar macrophages.
过氧化物酶体增殖物激活受体-γ（PPARγ）是一种参与脂质代谢的核转录因子，在健康个体的肺泡巨噬细胞中持续表达。PPARγ 最近被牵连到肺泡巨噬细胞中表面活性剂的分解代谢中，特别是表面活性剂的胆固醇成分，而其机制尚不清楚。来自其他组织巨噬细胞的研究表明，PPARγ 调节胆固醇的内流、外流和代谢。PPARγ 通过肝 X 受体-α（LXRα）和 ATP 结合盒 G1（ABCG1）促进胆固醇外流。我们最近表明，巨噬细胞特异性 PPARγ 敲除（PPARγ KO）小鼠积累富含胆固醇的肺泡巨噬细胞，表现出 LXRα 和 ABCG1 表达减少以及胆固醇外流减少。我们假设，除了这些胆固醇外流基因的失调外，参与胆固醇合成和内流的基因的表达也失调，并且替代 PPARγ 将恢复这些基因的调节。为了验证这一假设，我们利用慢病毒表达系统（Lenti-PPARγ）在 PPARγ KO 小鼠的肺泡巨噬细胞中恢复 PPARγ 的表达。我们的结果表明，PPARγ KO 小鼠的肺泡巨噬细胞中关键胆固醇合成基因的表达降低，胆固醇受体 CD36 和清道夫受体 A-I（SRA-I）的表达增加。替代 PPARγ（1）诱导 LXRα 和 ABCG1 的转录；（2）纠正了受抑制的胆固醇合成基因的表达；（3）增强了清道夫受体 CD36 的表达。这些结果表明，PPARγ 调节肺泡巨噬细胞中的胆固醇代谢。
