Gong Haibiao, He Jinhan, Lee Jung Hoon, Mallick Edward, Gao Xiang, Li Song, Homanics Gregg E, Xie Wen
Department of Pharmaceutical Sciences, Center for Pharmacogenetics, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, USA.
J Biol Chem. 2009 Oct 30;284(44):30113-21. doi: 10.1074/jbc.M109.047753. Epub 2009 Aug 29.
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 LXRalpha and LXRbeta 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 LXRalpha in vivo including the pulmonary function of this LXR isoform, we created LXRalpha knock-in (LXR-KI) mice in which a constitutively activated LXRalpha (VP-LXRalpha) was inserted into the mouse LXRalpha 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.
肝脏X受体（LXRs）作为一种固醇感受器，已知其会影响胆固醇和脂质稳态以及炎症反应。尽管LXRs的肝脏功能已有充分记录，但LXRs在肺中是否发挥病理生理作用以及如何发挥作用在很大程度上仍不清楚。在此我们表明，LXRα和LXRβ在小鼠I型和II型肺上皮细胞以及人肺癌细胞中均有表达。为了研究LXRα在体内的作用，包括该LXR亚型的肺功能，我们构建了LXRα基因敲入（LXR-KI）小鼠，其中将组成型激活的LXRα（VP-LXRα）插入到小鼠LXRα基因座中。我们发现，LXR-KI小鼠或经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小鼠和经LXR配体处理的野生型小鼠对脂多糖诱导的肺损伤表现出显著抗性，且活性氧的产生减少。总之，我们揭示了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。
