Liver X receptor (LXR) (LXR)

Liver X receptors (LXRs) are members of the nuclear hormone receptor superfamily of ligand-activated transcription factors, consisting of two subtypes: LXR alpha (NR1H3), which is highly expressed in the liver, intestine, and adipose tissue, and LXR beta (NR1H2), which is ubiquitously expressed (UniProt P55055, Q13133). They function as metabolic sensors for oxysterols, which are cholesterol-derived molecules, and play a central role in maintaining whole-body cholesterol homeostasis by promoting reverse cholesterol transport. Activation of LXRs stimulates the expression of transporters like ABCA1 and ABCG1, which facilitate the efflux of cholesterol from peripheral tissues, such as macrophages, to high-density lipoproteins (HDL) for eventual excretion (PMID: 29453248). Beyond lipid metabolism, LXRs exert potent anti-inflammatory effects by transrepressing pro-inflammatory genes in immune cells, making them potential targets for atherosclerosis and neurodegenerative diseases like Alzheimer's (PMID: 12517870, 17329404). While they are promising therapeutic targets, a significant challenge in drug development is the concurrent activation of hepatic lipogenesis via the SREBP-1c pathway, which can lead to elevated plasma triglycerides and fatty liver (PMID: 30108354). Current research focuses on developing tissue-selective or isoform-selective modulators to harness the cardiovascular and anti-inflammatory benefits while minimizing metabolic side effects.

Other names

NR1H3NR1H2Liver X receptor alphaLiver X receptor betaOxysterols receptorNuclear receptor subfamily 1 group H member 3Nuclear receptor subfamily 1 group H member 2

LXR agonists bind to the ligand-binding domain of LXR alpha or beta, inducing a conformational change that promotes heterodimerization with the Retinoid X Receptor (RXR). This complex binds to LXR response elements (LXREs) in the promoters of target genes, recruiting co-activators to initiate the transcription of genes involved in cholesterol efflux, such as ABCA1 and ABCG1 (PMID: 11030617, 29453248). In the context of inflammation, LXRs can transrepress pro-inflammatory genes by preventing the dismissal of corepressor complexes from NF-kappaB target promoters (PMID: 12517870).