Liver x receptor signaling pathways and atherosclerosis

Abstract

First discovered as orphan receptors, liver X receptors (LXRs) were subsequently identified as the nuclear receptor target of the cholesterol metabolites, oxysterols. There are 2 LXR receptors encoded by distinct genes: LXRalpha is most highly expressed in the liver, adipose, kidney, adrenal tissues, and macrophages and LXRbeta is ubiquitously expressed. Despite differential tissue distribution, these isoforms have 78% homology in their ligand-binding domain and appear to respond to the same endogenous ligands. Work over the past 10 years has shown that the LXR pathway regulates lipid metabolism and inflammation via both the induction and repression of target genes. Given the importance of cholesterol regulation and inflammation in the development of cardiovascular disease, it is not surprising that activation of the LXR pathway attenuates various mechanisms underlying atherosclerotic plaque development. In this brief review, we will discuss the impact of the LXR pathway on both cholesterol metabolism and atherosclerosis.

Figure 1. Effects of LXR agonist on cells of the vascular wall

ABC, ATP binding cassette transport; AT1R, angiotensin II receptor subtype 1; COX, cyclooxygenase; ICAM, intracellular adhesion molecule; Idol, inducible degrader of LDLR; IL, interleukin; iNOS, inducible nitric oxide synthase; MMP, matrix metalloproteinase; SCD, stearoyl-CoA desaturase; SMA, smooth muscle actin; VCAM, vascular cell adhesion molecule;