LXR Regulation And Function In Human Airway Smooth Muscle

Abstract

<p> The liver X receptors (LXRs) are members of the nuclear hormone receptor (NHR) superfamily of transcription factors and are activated by oxysterols. As such, LXRs act as "cholesterol sensors" and play an integral role in cholesterol homeostasis by modulating the expression of genes involved in lipid transport and metabolism as well as inflammation. </p> <p> This thesis begins by describing the modulation of LXR transactivation by PKC. Specifically, transactivation by LXRα is decreased upon activation of PKC signalling pathways as assessed by LXR reporter gene analysis and endogenous target gene expression. These findings reveal a mode of regulation of LXRα that may be relevant to disease conditions where aberrant PKC signalling is observed. </p> <p> The second and third part of the thesis turns the attention to the role of LXR in human airway smooth muscle (hASM), a crucial effector cell in asthma progression. For the first time, research described here indicates that primary human ASM cells express functional LXRs. Moreover, LXR target genes ABCA 1 and ABCG I were highly induced upon the addition of LXR agonists leading to enhanced cholesterol efflux to apoAI and HDL, a process dependant entirely on ABCA I. Furthermore, activation of LXR inhibited the expression of multiple cytokines in response to inflammatory mediators and inhibited the proliferation and migration of hASM cells, two important processes that contribute to the airway remodelling observed in the asthmatic lung. </p> <p> This body of work suggests that modulation of LXR offers prospects for new therapeutic approaches in the treatment of asthma. Furthermore, it establishes a critical role for ABCA 1 in lipid transport in ASM cells and suggests that dysregulation of cholesterol homeostasis in these cells may be important. These findings have broad implications in the association of hypercholesterolemia and AHR and places LXR at the forefront of novel therapeutic avenues to treat inflammatory lung disease. </p>