Liver X Receptor: Crosstalk Node for the Signaling of Lipid Metabolism, Carbohydrate Metabolism, and Innate Immunity

Abstract

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.

Keywords: Cholesterol; Inflammation; Innate Immunity; Liver X Receptor.

Figure 1. LXR integrates host metabolism and host defense

A theoretical cell, depicted as a macrophage, is shown to illustrate LXRs role in integrating cellular signals and processes. Ligands, such as oxysterols and glucose, bind to LXR in its heterodimeric complex with RXR, and induce its activation via co-activator for co-repressor exchange. LXR target genes (shown in red), including ABCA1, apoE, SREBP-1c, FAS, and GLUT4 are thereby induced, and contribute to cellular cholesterol efflux, lipogenesis, and glucose transport. Pathogen-associated molecular pattern ligands for TLR3 and TLR4 inhibit LXR via IRF3, whereas LXR attenuates pro-inflammatory gene (e.g., cytokine) expression through inhibition of NF-κB. Abbreviations: ABCA1 = ATP-binding cassette transporter A1; Apo = apolipoprotein; ER = endoplasmic reticulum; FAS = fatty acid synthase; GLUT4 = glucose transporter 4; IRF3 = interferon regulatory factor 3; LXR = Liver X Receptor; oxLDL = oxidized low density lipoprotein; RXR = Retinoid X Receptor; SREBP-1c = sterol regulatory element binding protein-1c; TLR = Toll like Receptor.