Liver X Receptors in Atherosclerosis and Inflammation

Abstract

Liver-X-receptors (LXRs) are cholesterol sensing nuclear receptors that are not only key regulators of lipid metabolism and transport, but they also suppress inflammatory signaling in macrophages through a unique mechanism of transrepression. In this brief review, we focus on the regulatory actions of LXR primarily in macrophages responding to a proatherogenic environment. LXR potentially interferes with atherosclerosis by two different agonist dependent signaling pathways. The first is through promoting reverse cholesterol transport (RCT) by directly activating genes of cellular cholesterol export. The second is through a general inhibitory action on pro-inflammatory genes where sumo-modified and agonist bound LXR recruits negative co-regulatory proteins to NF-κB at immune response gene promoters through protein-protein interactions. The anti-inflammatory actions of LXR may be a direct response to the pro-inflammatory actions recently proposed for cholesterol on inflammasome activity in the vessel wall.

Transcriptional Profiling of Foam Cells Reveals Induction of Guanylate‐Binding Proteins Following Western Diet Acceleration of Atherosclerosis in the Absence of Global Changes in Inflammation

“…For example, oxLDL was shown to activate NF‐κB by binding to Toll‐like receptors (TLRs) such as TLR2 and TLR4 35, 36. Accumulation of cholesterol crystals in the cytoplasm of macrophages was also proposed to stimulate a proinflammatory cascade 37. Alternatively, lipoprotein‐derived oxysterols are natural liver X receptor ligands, which can counter‐regulate induction of inflammatory gene expression by NF‐κB by recruiting corepressors to the promoters of inflammatory genes 37, 38, 39.…”

Sphingomyelin Phosphodiesterase Acid-like 3A (SMPDL3A) Is a Novel Nucleotide Phosphodiesterase Regulated by Cholesterol in Human Macrophages

“…Bioinformatic analysis of the genomic nucleic acid sequence upstream of the SMPDL3A ORF using MatInspector software (16) identified a potential LXR element 160 bp upstream from the transcription start site (sequence AGGTCAGGCGAACTGA). LXR elements were recognized by LXR-retinoid X receptor heterodimeric transcription complexes after activation by binding to oxysterol ligands and are important for the regulation of several key cholesterol-responsive genes, such as ABCA1 and ABCG1 (17). Treatment of HMDMs with the synthetic LXR ligand T-0901317 strongly stimulated SMPDL3A mRNA (Fig.…”

Effect of a high-fat diet on the hepatic expression of nuclear receptors and their target genes: relevance to drug disposition

“…The constitutive androstane receptor (CAR/NR1I3 (nuclear receptor subfamily 1, group I, member 3)) is another xenobiotic-sensing nuclear receptor, which regulates drug detoxification pathways through the induction of an overlapping set of genes, including Pgp, ABCC2, ABCC3 and CYP2B6 (cytochrome P450 2B6) (23) . Liver X receptor (LXRa/b/NR1H3/2 (nuclear receptor subfamily 1, group H, member 3/2)) is a main regulator of cholesterol metabolism, and has recently been shown to play a role in the pathogenesis of inflammation (24) . Oxysterols, the oxygenated derivatives of cholesterol, activate LXR, thereby promoting the clearance of cholesterol through the induction of several transporters including ABCA1, ABCG1 (ATP-binding cassette subfamily G member 1), ABCG5/ABCG8 as well as the sterol regulatory element-binding protein 1 that promotes TAG synthesis (25) .…”