New wrestling rules of anti-inflammatory transrepression by oxysterol receptor LXR revealed

Treuter, Eckardt

doi:10.1038/cr.2011.52

Cited by 11 publications

(5 citation statements)

References 15 publications

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“…The absence of an increase in TNFa secretion by BV2 cells pretreated with SFA, however, suggests either that this same pathway was not activated by SFA, or that SFA exerted additional regulatory effects on this pathway. Fatty acids are ligands for peroxisome proliferator activated receptors, liver X receptors, and other nuclear hormone receptors [32] that can act as corepressors upon docking to the promoters of primary-response inflammatory genes [33]. It is possible that 16:0 and 18:0 may have activated a corepressor pathway that modulated their effect on TNFa expression.…”

Section: Discussionmentioning

confidence: 99%

Microglial Cell Activation Increases Saturated and Decreases Monounsaturated Fatty Acid Content, but Both Lipid Species are Proinflammatory

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Mitchell

Domingos

et al. 2014

Lipids

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Neuroinflammation is a component of age-related neurodegenerative diseases and cognitive decline. Saturated (SFA) and monounsaturated (MUFA) fatty acids are bioactive molecules that may play different extrinsic and intrinsic roles in neuroinflammation, serving as exogenous ligands for cellular receptors, or endogenous components of cell structural, energetic and signaling pathways. We determined the fatty acyl profile of BV2 microglial cells before and after acute activation with lipopolysaccharide (LPS). We also investigated the effect of SFA and MUFA pretreatment on the production of an invasive, neurotoxic phenotype in BV2 cells. Acute activation of BV2 microglia resulted in an increase in the relative content of SFA (12:0, 16:0, 18:0, 20:0, 22:0, and 24:0 increased significantly), and a relative decrease in the content of MUFA (16:1n7, 18:1n7, 18:1n9, 20:1n9, 24:1n9 decreased significantly). In agreement, the major stearoyl-CoA desaturase (SCD) isoform in BV2 cells, SCD2, was significantly down-regulated by LPS. We next treated cells with SFA (16:0 or 18:0) or MUFA (16:1n7 or 18:1n9), and found that levels of secreted IL6 were increased, as was secreted MMP9-mediated proteolytic activity. To test the functional significance, we treated SH-SY5Y neuronal cells with conditioned medium from BV2 cells pretreated with fatty acids, and found a small but significant induction of cell death. Our findings suggest differential intrinsic roles for SFA and MUFA in activated microglial cells, but similar extrinsic roles for these fatty acid species in inducing activation. Expansion of SFA is important during microglial cell activation, but either supplemental SFA or MUFA may contribute to chronic low-grade neuroinflammation.

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Section: Discussionmentioning

confidence: 99%

Microglial Cell Activation Increases Saturated and Decreases Monounsaturated Fatty Acid Content, but Both Lipid Species are Proinflammatory

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Mitchell

Domingos

et al. 2014

Lipids

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“…Joseph et al [82] first demonstrated that activation of LXR attenuated the expression of proinflammatory factors such as IL-6, inducible nitric oxide synthase (iNOS) and COX-2, as well as MMP-9, in macrophages treated with E.coli or lipopolysaccharide; consistently, a recent study employing mice expressing constitutively active VP16-LXRa in macrophages and adipocytes demonstrated that the macrophages were protected against inflammatory stimuli [83 & ]. The underlying mechanism, termed transrepression, involves post-translational modification of the LXRs by small ubiquitin-like modifiers (SUMOs) [39,84], the SUMOylated LXRs preventing the clearance of corepressors from promoters of target genes otherwise induced by proinflammatory stimuli [85][86][87]. The underlying mechanism, termed transrepression, involves post-translational modification of the LXRs by small ubiquitin-like modifiers (SUMOs) [39,84], the SUMOylated LXRs preventing the clearance of corepressors from promoters of target genes otherwise induced by proinflammatory stimuli [85][86][87].…”

Section: Oxysterols Suppress Macrophage Inflammatory Activity Via LIVmentioning

confidence: 99%

Macrophage oxysterols and their binding proteins

Olkkonen¹

2012

Current Opinion in Lipidology

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“…All these proteins are transcription factors that interact with response elements found in a multitude of genes engaged in lipid turnover including their own genes. Moreover, LXRs and PPARs were found to participate in negative regulation of pro-inflammatory genes while, in turn, being the objects of inflammatory stimuli (reviewed in [8], [9]). It is not fully understood why the system of lipid homeostasis fails to prevent foam cell formation and following plaque development.…”

Section: Introductionmentioning

confidence: 99%

Lipid Regulators during Atherogenesis: Expression of LXR, PPAR, and SREBP mRNA in the Human Aorta

et al. 2013

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Transcription factors LXRs, PPARs, and SREBPs have been implicated in a multitude of physiological and pathological processes including atherogenesis. However, little is known about the regulation of these transcription factors at different stages of atherosclerosis progression. Quantitative real-time polymerase chain reaction (qRT-PCR) was used to compare the contents of mRNAs in pairs intact-injured aorta fragments taken from the same donors. Only minor changes in LXRα, LXRβ, PPARα, PPARγ, SREBP1, and SREBP2 mRNA levels were found in initial lesions as compared with intact non-diseased tissue. The contents of all mRNAs but SREBP2 mRNA were found to be progressively up-regulated in fatty streaks and fibrous lipoid plaques. These changes were only partially reproduced in cultured macrophages upon lipid loading. Wave-shaped changes in abundance of correlations between given group of mRNAs and 28 atherosclerosis-related mRNA species in the course of atherogenesis were observed. The impact of specific mRNA correlations on the total correlations also significantly varied between different lesion types. The study suggests that the extent and forms of LXR/PPAR/SREBP participation in intima functions vary nonlinear in individual fashion in atherogenesis. We speculate that the observed changes in mRNAs expression and coupling reflect shifts in lipid ligands availability and cellular composition in the course of atherosclerosis progression.

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New wrestling rules of anti-inflammatory transrepression by oxysterol receptor LXR revealed

Cited by 11 publications

References 15 publications

Microglial Cell Activation Increases Saturated and Decreases Monounsaturated Fatty Acid Content, but Both Lipid Species are Proinflammatory

Microglial Cell Activation Increases Saturated and Decreases Monounsaturated Fatty Acid Content, but Both Lipid Species are Proinflammatory

Macrophage oxysterols and their binding proteins

Lipid Regulators during Atherogenesis: Expression of LXR, PPAR, and SREBP mRNA in the Human Aorta

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