Activation of the Liver X Receptor Prevents Lipopolysaccharide-induced Lung Injury
Activation of the Liver X Receptor Prevents Lipopolysaccharide-induced Lung Injury
复制标题
DOI：
10.1074/jbc.m109.047753
复制
发表时间：
2009-10-30
影响因子：
4.8
通讯作者：
Xie, Wen
中科院分区：
文献类型：
--
作者：
Gong, Haibiao;He, Jinhan;Xie, Wen
肝脏X受体(LXRs)被认为是影响胆固醇和脂质动态平衡以及炎症的类固醇传感器。虽然LXRs的肝脏功能已有很好的文献记载，但LXRs是否以及如何在肺中发挥病理生理作用仍很大程度上尚不清楚。在这里，我们发现LXRα和LXRβ在I型和II型小鼠肺上皮细胞以及人肺癌细胞中都有表达。为了研究LXRα在体内的作用，包括这种LXR亚型的肺功能，我们创建了LXRα敲入(LXR-KI)小鼠，在小鼠的LXRα基因座上插入了一个成分激活的LXRα(VP-LXRα)。我们发现，在LXR-KI小鼠或LXR激动剂处理的野生型小鼠中，LXR的激活诱导了编码多种抗氧化酶的基因在肺中的表达。与抗氧化酶的诱导一致，LXR-Ki小鼠和LXR配体处理的野生型小鼠对内毒素诱导的肺损伤表现出显著的抵抗力，并减少了活性氧的产生。综上所述，我们发现了LXR在调节肺中抗氧化酶方面的新作用，以及这种调节在肺组织保护中的意义。
The liver X receptors (LXRs) have been known as sterol sensors that impact cholesterol and lipid homeostasis, as well as inflammation. Although the hepatic functions of LXRs are well documented, whether and how LXRs play a pathophysiological role in the lung remain largely unknown. Here we show that LXR alpha and LXR beta are expressed in both type I and type II mouse lung epithelial cells, as well as in human lung cancer cells. To study the role of LXR alpha in vivo including the pulmonary function of this LXR isoform, we created LXR alpha knock-in (LXR-KI) mice in which a constitutively activated LXR alpha (VP-LXR alpha) was inserted into the mouse LXR alpha locus. We show that activation of LXR in LXR-KI mice or LXR agonist-treated wild type mice induced pulmonary expression of genes encoding multiple antioxidant enzymes. Consistent with the induction of antioxidant enzymes, LXR-KI mice and LXR ligand-treated wild type mice showed a substantial resistance to lipopolysaccharide-induced lung injury and decreased production of reactive oxygen species. In summary, we have uncovered a novel role of LXR in regulating antioxidant enzymes in the lung and the implication of this regulation in pulmonary tissue protection.