👤 Michael B Fessler

Liver X Receptor-α (LXRα, also known as NR1H3) and LXRβ (NR1H2) are members of the nuclear receptor superfamily of ligand-activated transcription factors, a superfamily which includes the more widely known glucocorticoid receptor, estrogen receptor, thyroid receptor, and peroxisome proliferator-activated receptors. The LXRs are activated by physiologic sterol ligands (e.g., oxysterols) and by synthetic agonists. In recent years, our understanding of the importance of LXRs has expanded across several fields of (patho-)physiology. Perhaps best known from a sizeable literature as homeostatic 'cholesterol sensors' that drive transcriptional programs promoting cellular cholesterol efflux, 'reverse cholesterol transport,' and bile acid synthesis, more recent roles for LXRs in glucose homeostasis, atherosclerosis, and innate immunity have also been identified. These discoveries complement an emerging literature that continues to draw surprisingly intimate connections between host metabolism and host defense. The present review will discuss the roles of LXR in the signaling of metabolism and innate immunity, and the potential for synthetic LXR agonists as novel therapeutics in dyslipidemia, atherosclerosis, disordered glucose metabolism, and inflammation. Show less

Liver X receptor (LXR) alpha and beta are members of the nuclear receptor superfamily of ligand-activated transcription factors. Best known for triggering "reverse cholesterol transport" gene programs upon their activation by endogenous oxysterols, LXRs have recently also been implicated in regulation of innate immunity. In this study, we define a role for LXRs in regulation of pulmonary inflammation and host defense and identify the lung and neutrophil as novel in vivo targets for pharmacologic LXR activation. LXR is expressed in murine alveolar macrophages, alveolar epithelial type II cells, and neutrophils. Treatment of mice with TO-901317, a synthetic LXR agonist, reduces influx of neutrophils to the lung triggered by inhaled LPS, intratracheal KC chemokine, and intratracheal Klebsiella pneumoniae and impairs pulmonary host defense against this bacterium. Pharmacologic LXR activation selectively modulates airspace cytokine expression induced by both LPS and K. pneumoniae. Moreover, we report for the first time that LXR activation impairs neutrophil motility and identify inhibition of chemokine-induced RhoA activation as a putative underlying mechanism. Taken together, these data define a novel role for LXR in lung pathophysiology and neutrophil biology and identify pharmacologic activation of LXR as a potential tool for modulation of innate immunity in the lung. Show less