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 LXR␣ and LXR␤ 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␣ in vivo including the pulmonary function of this LXR isoform, we created LXR␣ knock-in (LXR-KI) mice in which a constitutively activated LXR␣ (VP-LXR␣) was inserted into the mouse LXR␣ 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.

Ozone-derived Oxysterols Affect Liver X Receptor (LXR) Signaling

“…LXR activation by synthetic agonists leads to decreased neutrophil recruitment and increased bacterial burden, indicating that LXR activation balance contributes to host immune defense (46). Recent studies also suggest that LXR agonists show therapeutic promise in treating lung disorders such as dyslipidemia and asthma (43,47,48). Furthermore, our data show that O 3 exposure of LXR␣ Ϫ/Ϫ mice results in enhanced pro-inflammatory response, indicating the importance of normal LXR␣ activity to regulate O 3 -induced inflammation (Fig.…”

Decreased serum level of lipoprotein cholesterol is a poor prognostic factor for patients with severe community-acquired pneumonia that required intensive care unit admission

“…Recent studies have revealed important roles for cholesterol regulators on pulmonary immune responses to the lung injury and infection [29][30][31][32]. The exact pathophysiological mechanisms of cholesterol in severe illness and sepsis have never been fully understood.…”

Plasma PLTP (phospholipid-transfer protein): an emerging role in ‘reverse lipopolysaccharide transport’ and innate immunity

“…A protective role of LXR agonists against LPS-mediated tissue injury has been demonstrated in vivo in the liver and the lung [50,51]. LXR is also able to regulate the expression of proteins potentially involved in LPS detoxification such as PLTP and CETP [52,53].…”