Figure 1. Molecular mechanisms of LXR action.

Genomic mechanisms, including gene transactivation (A) and transrepression (B), are the best characterized means of LXR activity in cells, whereas recently described non-genomic mechanisms (C) remain somewhat less well understood. In transactivation, two general models, represented by induction of the target genes ATP Binding Cassette (ABC)A1 and ABCG1, have been identified. For ABCA1, it is thought that LXR bound to promoter LXR response elements (LXREs) in the steady state tonically represses gene expression by recruiting co-repressors such as nuclear receptor co-repressor 1 (NCoR). Upon LXR ligand binding, co-repressors are shed in exchange for co-activators, driving gene expression. More recent studies suggest that for a majority of LXR targets including ABCG1, LXRs bind to LXREs only after ligand-induced activation and histone demethylation. In both of these models, LXR binds LXREs directly in the form of a heterodimer with retinoid X receptor (RXR). In the case of transrepression of pro-inflammatory genes (B), two general mechanisms of LXR action have been identified in macrophages/hepatocytes and astrocytes. In both cases, lysines in the ligand-binding domain of LXR are SUMOylated after LXR ligation. In the case of LPS-stimulated macrophages or cytokine-stimulated hepatocytes, SUMOylated LXR binds in monomeric form to a multimolecular co-repressor complex, inhibiting release of co-repressors from gene promoters, thereby blocking gene expression. In astrocytes, SUMOylated LXRs inhibit transcription by blocking the binding of signal transducer and activator of transcription 1 (STAT1) to promoters. Recently, examples of non-genomic (extranuclear) LXRβ action have been identified, as shown in panel C. In colon cancer cells, cytoplasmic LXRβ drives NLRP3- and caspase-1-dependent pyroptotic cell death by inducing pannexin-1-mediated ATP release. In platelets, LXRβ inhibits kinase signaling to degranulation and aggregation downstream of the GPVI receptor. In endothelial cells, lipid raft-localized LXRβ mediates a signaling pathway to cell migration involving estrogen receptor (ER)-α and the kinase AKT. The relative importance of genomic and non-genomic mechanisms remains poorly understood. The distinct binding partners of LXRs in these various contexts, however, creates the exciting potential for targeted, potentially cell type- and gene-specific, pharmacologic interventions. eNOS, endothelial nitric oxide synthase; GPVI, glycoprotein VI; GPS2, G-protein pathway suppressor 2; HDAC, histone deacetylase; iNOS, inducible nitric oxide synthase; P2X7, P2X purinoceptor 7; PIAS1, protein inhibitor of STAT1; SAA, serum amyloid A; SUMO, small ubiquitin-like modifier; TBLR, transducin beta-like 1X-related protein 1; UBC9, SUMO-conjugating enzyme UBC9.