Activation of the liver X receptor prevents lipopolysaccharide-induced lung injury.
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.
Gong
Haibiao
H
Department of Pharmaceutical Sciences, Center for Pharmacogenetics, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, USA.
He
Jinhan
J
Lee
Jung Hoon
JH
Mallick
Edward
E
Gao
Xiang
X
Li
Song
S
Homanics
Gregg E
GE
Xie
Wen
W
D000818:Animals; D004847:Epithelial Cells; D015870:Gene Expression; D006801:Humans; D008070:Lipopolysaccharides / Q000633:toxicity*; D000071518:Liver X Receptors; D008168:Lung / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D055370:Lung Injury / Q000139:chemically induced / Q000209:etiology*; D008175:Lung Neoplasms / Q000473:pathology; D051379:Mice; D057093:Orphan Nuclear Receptors / Q000378:metabolism* / Q000502:physiology; D010088:Oxidoreductases / Q000235:genetics
D008070:Lipopolysaccharides; D000071518:Liver X Receptors; C000605213:NR1H3 protein, human; C000605214:Nr1h3 protein, mouse; D057093:Orphan Nuclear Receptors; D010088:Oxidoreductases