Reciprocal Negative Cross-Talk between Liver X Receptors (LXRs) and STAT1: Effects on IFN-γ–Induced Inflammatory Responses and LXR-Dependent Gene Expression

Abstract

Liver X receptors (LXRs) exert key functions in lipid homeostasis and in control of inflammation. In this study we have explored the impact of LXR activation on the macrophage response to the endogenous inflammatory cytokine IFN-γ. Transcriptional profiling studies demonstrate that ∼38% of the IFN-γ–induced transcriptional response is repressed by LXR activation in macrophages. LXRs also mediated inhibitory effects on selected IFN-γ–induced genes in primary microglia and in a model of IFN-γ–induced neuroinflammation in vivo. LXR activation resulted in reduced STAT1 recruitment to the promoters tested in this study without affecting STAT1 phosphorylation. A closer look into the mechanism revealed that SUMOylation of LXRs, but not the presence of nuclear receptor corepressor 1, was required for repression of the NO synthase 2 promoter. We have also analyzed whether IFN-γ signaling exerts reciprocal effects on LXR targets. Treatment with IFN-γ inhibited, in a STAT1-dependent manner, the LXR-dependent upregulation of selective targets, including ATP-binding cassette A1 (ABCA1) and sterol response element binding protein 1c. Downregulation of ABCA1 expression correlated with decreased cholesterol efflux to apolipoprotein A1 in macrophages stimulated with IFN-γ. The inhibitory effects of IFN-γ on LXR signaling did not involve reduced binding of LXR/retinoid X receptor heterodimers to target gene promoters. However, overexpression of the coactivator CREB-binding protein/p300 reduced the inhibitory actions of IFN-γ on the Abca1 promoter, suggesting that competition for CREB-binding protein may contribute to STAT1-dependent downregulation of LXR targets. The results from this study suggest an important level of bidirectional negative cross-talk between IFN-γ/STAT1 and LXRs with implications both in the control of IFN-γ–mediated immune responses and in the regulation of lipid metabolism.

Anti-diabetic rosiglitazone remodels the adipocyte transcriptome by redistributing transcription to PPARγ-driven enhancers

“…A role for coactivator redistribution or squelching has been previously suggested to explain transcriptional repression by NRs, but most of those studies were performed using transfection to overexpress receptors or coactivators and used reporter genes as readouts (Kamei et al 1996;Fronsdal et al 1998;Lee et al 2000;Li et al 2000;Kim et al 2001;Zhang and Teng 2001;Manna and Stocco 2007;He et al 2012;Pascual-Garcia et al 2013). This model gained further support recently with evidence that the endogenous coactivator NCOA3 is lost from sites of diminished DNase I hypersensitivity upon E2 hormone treatment in MCF-7 cells (He et al 2012).…”

“…Support for this coactivator competition model, often referred to as squelching, has been largely based on TF overexpression experiments in transfection systems (Gill and Ptashne 1988;Kelleher et al 1990; Kamei et al 1996;Fronsdal et al 1998;Lee et al 2000;Li et al 2000;Kim et al 2001;Zhang and Teng 2001;Manna and Stocco 2007;He et al 2012;Pascual-Garcia et al 2013), although a recent study demonstrated coactivator redistribution with endogenous factors and chromatin on a genome-wide scale in the context of E2-treated MCF-7 cells (He et al 2012).…”

Posttranslational Modifications of Lipid-Activated Nuclear Receptors: Focus on Metabolism

“…Moreover, a later study showed that mutant forms of both LXRs lacking SUMO acceptor sites (LXR α K328R/K434R and LXR β K410R/K448R) (Fig. 1) have a decreased capacity to prevent the binding of the proinflammatory signal transducer and activator of transcription 1 transcription factor to the Nos2 promoter (59), further establishing the importance of LXR SUMOylation on its transrepressive capacity. However, this transrepression model has now been challenged.…”

SUMOylation: Novel Neuroprotective Approach for Alzheimer’s Disease?

“…In cultured macrophages, peroxisome proliferator-activated receptor-gamma (PPAR-γ) and LXRs have been found to be SUMOylated, which regulates the transrepression of inflammatory response genes [50]. SUMOylation is usually associated with a cytoprotective response to cellular stressors.…”