Activation of the liver X receptor prevents lipopolysaccharide-induced lung injury

Abstract

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 LXRa and LXRβ 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 LXRα in vivo including the pulmonary function of this LXR isoform, we created LXRa knock-in (LXR-KI) mice in which a constitutively activated LXRa (VP-LXRα) was inserted into the mouse LXRα locus.Weshow 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. © 2009 by The American Society for Biochemistry and Molecular Biology, Inc.