Liver X Receptor-Retinoid X Receptor (LXR-RXR) Heterodimer Cistrome Reveals Coordination of LXR and AP1 Signaling in Keratinocytes

Shen, Qi; Bai, Yunfeng; Chang, Ken C. N.; Wang, Yongjun; Burris, Thomas P.; Freedman, Leonard P.; Thompson, Catherine C.; Nagpal, Sunil

doi:10.1074/jbc.m110.165704

Cited by 46 publications

(29 citation statements)

References 45 publications

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“…This fits with the observations of the two presently published mouse LXR ChIP-Seq studies, where only 6.3% [18] or up to 8% [19] of the LXR peaks contained a DR4-type RE. In a very recent ChIP-on-chip report, 2035 LXRβ-RXR binding sites were identified within promoter regions of normal human epidermal keratinocytes [40]. Although 1666 (82%) of these rather large genomic fragments contain a kind of DR4-type RE, only 142 (7.0%) of them are highly scored, resulting in a very similar percentage as in our human and the mouse ChIP-Seq studies.…”

Section: Discussionsupporting

confidence: 73%

Genome-wide landscape of liver X receptor chromatin binding and gene regulation in human macrophages

et al. 2012

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BackgroundThe liver X receptors (LXRs) are oxysterol sensing nuclear receptors with multiple effects on metabolism and immune cells. However, the complete genome-wide cistrome of LXR in cells of human origin has not yet been provided.ResultsWe performed ChIP-seq in phorbol myristate acetate-differentiated THP-1 cells (macrophage-type) after stimulation with the potent synthetic LXR ligand T0901317 (T09). Microarray gene expression analysis was performed in the same cellular model. We identified 1357 genome-wide LXR locations (FDR < 1%), of which 526 were observed after T09 treatment. De novo analysis of LXR binding sequences identified a DR4-type element as the major motif. On mRNA level T09 up-regulated 1258 genes and repressed 455 genes. Our results show that LXR actions are focused on 112 genomic regions that contain up to 11 T09 target genes per region under the control of highly stringent LXR binding sites with individual constellations for each region. We could confirm that LXR controls lipid metabolism and transport and observed a strong association with apoptosis-related functions.ConclusionsThis first report on genome-wide binding of LXR in a human cell line provides new insights into the transcriptional network of LXR and its target genes with their link to physiological processes, such as apoptosis.The gene expression microarray and sequence data have been submitted collectively to the NCBI Gene Expression Omnibus http://www.ncbi.nlm.nih.gov/geo under accession number GSE28319.

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Section: Discussionsupporting

confidence: 73%

Genome-wide landscape of liver X receptor chromatin binding and gene regulation in human macrophages

et al. 2012

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“…This cross-talk was also observed in the LXRE present in the promoters of LXR target genes such as ABCA1, ABCG1, and LXRα itself. A previous genome-wide cistrome analysis revealed an enrichment of AP1 motifs at a location adjacent to the LXR-RXR heterodimer binding sites13. Consistently, we found that the LXRE located in the promoter of LXRα or ABCA1 overlapped with an AP1 motif, 5′-TGACCAG-3′ or 5′-TGACCGA-3′, respectively.…”

Section: Discussionsupporting

confidence: 88%

The trisaccharide raffinose modulates epidermal differentiation through activation of liver X receptor

Kim

et al. 2017

Sci Rep

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The epidermal barrier function requires optimal keratinocyte differentiation and epidermal lipid synthesis. Liver X receptor (LXR) α and β, are important transcriptional regulators of the epidermal gene expression. Here, we show that raffinose, a ubiquitously present trisaccharide in plants, activated the transcriptional activity of LXRα/β, which led to the induction of genes required for keratinocyte differentiation such as involucrin and filaggrin, and genes involved in lipid metabolism and transport including SCD1 and ABCA1 in both HaCaT and normal human epidermal keratinocytes. Raffinose induced the expression of JunD and Fra1, and their DNA binding in the AP1 motif in the promoters of involucrin and loricrin. Interestingly, LXR bound the AP1 motif upon raffinose treatment, and conversely, JunD and Fra1 bound the LXR response element in promoters of LXR target genes, which indicates the presence of a postive cross-talk between LXR and AP1 in the regualtion of these genes. Finally, the effect of raffinose in epidermal barrier function was confirmed by applying raffinose in an ointment formulation to the skin of hairless mice. These findings suggest that raffinose could be examined as an ingredient in functional cosmetics and therapeutic agents for the treatment of cutaneous disorders associated with abnormal epidermal barrier function.

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“…Furthermore, our results showed that formation of a LXRα/RXRα heterodimer and binding of LXRα to LXE of the abca1 promoter were reduced by high glucose, even though high glucose increased RXRα expression. It has been well documented that activated LXR stimulates formation of a heterodimer with RXR and controls transcriptional activity of the abca1 gene6263. Indeed, Repa et al .…”

Section: Discussionmentioning

confidence: 99%

High glucose upregulates BACE1-mediated Aβ production through ROS-dependent HIF-1α and LXRα/ABCA1-regulated lipid raft reorganization in SK-N-MC cells

Lee

Ryu

Jung

et al. 2016

Sci Rep

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There is an accumulation of evidence indicating that the risk of Alzheimer’s disease is associated with diabetes mellitus, an indicator of high glucose concentrations in blood plasma. This study investigated the effect of high glucose on BACE1 expression and amyloidogenesis in vivo, and we present details of the mechanism associated with those effects. Our results, using ZLC and ZDF rat models, showed that ZDF rats have high levels of amyloid-beta (Aβ), phosphorylated tau, BACE1, and APP-C99. In vitro result with mouse hippocampal neuron and SK-N-MC, high glucose stimulated Aβ secretion and apoptosis in a dose-dependent manner. In addition, high glucose increased BACE1 and APP-C99 expressions, which were reversed by a reactive oxygen species (ROS) scavenger. Indeed, high glucose increased intracellular ROS levels and HIF-1α expression, associated with regulation of BACE1 and Liver X Receptor α (LXRα). In addition, high glucose induced ATP-binding cassette transporter A1 (ABCA1) down-regulation, was associated with LXR-induced lipid raft reorganization and BACE1 localization on the lipid raft. Furthermore, silencing of BACE1 expression was shown to regulate Aβ secretion and apoptosis of SK-N-MC. In conclusion, high glucose upregulates BACE1 expression and activity through HIF-1α and LXRα/ABCA1-regulated lipid raft reorganization, leading to Aβ production and apoptosis of SK-N-MC.

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Liver X Receptor-Retinoid X Receptor (LXR-RXR) Heterodimer Cistrome Reveals Coordination of LXR and AP1 Signaling in Keratinocytes

Cited by 46 publications

References 45 publications

Genome-wide landscape of liver X receptor chromatin binding and gene regulation in human macrophages

Genome-wide landscape of liver X receptor chromatin binding and gene regulation in human macrophages

The trisaccharide raffinose modulates epidermal differentiation through activation of liver X receptor

High glucose upregulates BACE1-mediated Aβ production through ROS-dependent HIF-1α and LXRα/ABCA1-regulated lipid raft reorganization in SK-N-MC cells

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