Regulation of peroxisome proliferator‐activated receptors (PPAR) α and ‐γ of rat brain astrocytes in the course of activation by toll‐like receptor agonists

Chistyakov, Dmitry V.; Aleshin, Stepan; Astakhova, A. A.; Sergeeva, Marina G.; Reiser, Georg

doi:10.1111/jnc.13101

Cited by 47 publications

(28 citation statements)

References 52 publications

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“…Although we failed to observe an anti‐inflammatory effect of GW0742 in iPSC‐astrocytes, others have reported that PPARβ/δ activation alleviates astrocytic pro‐inflammatory activation (Chistyakov, Aleshin, Astakhova, Sergeeva, & Reiser, ). In contrast, the impact of GW0742 on suppression of inflammation may be model dependent, as Schnegg et al reported that GW0742 inhibited neuroinflammation, yet failed to restore neurogenesis or prevent hippocampal dependent cognitive deficits (Schnegg et al, ).…”

Section: Discussioncontrasting

confidence: 84%

PPARβ/δ‐agonist GW0742 ameliorates dysfunction in fatty acid oxidation in PSEN1ΔE9 astrocytes

Konttinen

Gureviciene

Oksanen

et al. 2018

Glia

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Astrocytes are the gatekeepers of neuronal energy supply. In neurodegenerative diseases, bioenergetics demand increases and becomes reliant upon fatty acid oxidation as a source of energy. Defective fatty acid oxidation and mitochondrial dysfunctions correlate with hippocampal neurodegeneration and memory deficits in Alzheimer's disease (AD), but it is unclear whether energy metabolism can be targeted to prevent or treat the disease. Here we show for the first time an impairment in fatty acid oxidation in human astrocytes derived from induced pluripotent stem cells of AD patients. The impairment was corrected by treatment with a synthetic peroxisome proliferator activated receptor delta (PPARβ/δ) agonist GW0742 which acts to regulate an array of genes governing cellular metabolism. GW0742 enhanced the expression of CPT1a, the gene encoding for a rate‐limiting enzyme of fatty acid oxidation. Similarly, treatment of a mouse model of AD, the APP/PS1‐mice, with GW0742 increased the expression of Cpt1a and concomitantly reversed memory deficits in a fear conditioning test. Although the GW0742‐treated mice did not show altered astrocytic glial fibrillary acidic protein‐immunoreactivity or reduction in amyloid beta (Aβ) load, GW0742 treatment increased hippocampal neurogenesis and enhanced neuronal differentiation of neuronal progenitor cells. Furthermore, GW0742 prevented Aβ‐induced impairment of long‐term potentiation in hippocampal slices. Collectively, these data suggest that PPARβ/δ‐agonism alleviates AD related deficits through increasing fatty acid oxidation in astrocytes and improves cognition in a transgenic mouse model of AD.

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Section: Discussioncontrasting

confidence: 84%

PPARβ/δ‐agonist GW0742 ameliorates dysfunction in fatty acid oxidation in PSEN1ΔE9 astrocytes

Konttinen

Gureviciene

Oksanen

et al. 2018

Glia

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“…Toll-like receptor (TLR) agonists reduce the mRNA, protein levels and activity of PPARγ, which is crucial for inflammation response in rat brain astrocytes [30]. These existing researches leaded us to investigate whether reciprocation between PPARγ and TLR4 contributed to inflammation in LPS-stimulated endothelial EA.hy926 cells.…”

Section: Resultsmentioning

confidence: 99%

Interactions of TLR4 and PPARγ, Dependent on AMPK Signalling Pathway Contribute to Anti-Inflammatory Effects of Vaccariae Hypaphorine in Endothelial Cells

Sun¹,

Zhu²,

Lin³

et al. 2017

Cell Physiol Biochem

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Background /Aims: Accumulating evidence indicates that endothelial inflammation is one of the critical determinants in pathogenesis of atherosclerotic cardiovascular disease. Our previous studies had demonstrated that Vaccariae prevented high glucose or oxidative stress-triggered endothelial dysfunction in vitro. Very little is known about the potential effects of hypaphorine from Vaccariae seed on inflammatory response in endothelial cells. Methods: In the present study, we evaluated the anti-inflammatory effects of Vaccariae hypaphorine (VH) on lipopolysaccharide (LPS)-challenged endothelial EA.hy926 cells. The inflammatory cytokines including tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), monocyte chemoattractant protein 1 (MCP-1) and vascular cellular adhesion molecule-1 (VCAM-1) were measured by real-time PCR (RT-PCR). The expressions of adenosine monophosphate-activated protein kinase (AMPK), acetyl-CoA carboxylase (ACC), toll-like receptor 4 (TLR4), peroxisome proliferator-activated receptor γ (PPARγ) were detected by Western blotting or immunofluorescence. Results: We showed that LPS stimulated the expressions of TNF-α, IL-1β, MCP-1, VCAM-1 and TLR4, but attenuated the phosphorylation of AMPK and ACC as well as PPARγ protein levels, which were reversed by VH pretreatment. Moreover, we observed that LPS-upregulated TLR4 protein expressions were inhibited by PPARγ agonist pioglitazone, and the downregulated PPARγ expressions in response to LPS were partially restored by knockdown of TLR4. The negative regulation loop between TLR4 and PPARγ response to LPS was modulated by AMPK agonist AICAR (5-Aminoimidazole-4-carboxamide riboside or acadesine) or A769662. Conclusions: Taken together, our results suggested that VH ameliorated LPS-induced inflammatory cytokines production in endothelial cells via inhibition of TLR4 and activation of PPARγ, dependent on AMPK signalling pathway.

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“…The impact of proinflammatory factors on NF-κB is accompanied by the synthesis of prostaglandins D2 and E2 (PGD2 and PGE2) activating PPARα and PPARγ. C-Jun-NH2-terminal kinase (JNK) and p38 mitogen-activated protein kinase (P38MAPK), which are members of the signaling pathways of mitogenactivated protein kinase (MAPK) cascades, are involved in the regulation of PPAR expression [49,50]. Activated PPARs (all isoforms) inhibit NF-κB activity, leading to the suppression of inflammation.…”

Section: Ppar Researchmentioning

confidence: 99%

Peroxisome Proliferator-Activated Receptors as a Therapeutic Target in Asthma

et al. 2020

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The complexity of the pathogenetic mechanisms of the development of chronic inflammation in asthma determines its heterogeneity and insufficient treatment effectiveness. Nuclear transcription factors, which include peroxisome proliferatoractivated receptors, that is, PPARs, play an important role in the regulation of initiation and resolution of the inflammatory process. The ability of PPARs to modulate not only lipid homeostasis but also the activity of the inflammatory response makes them an important pathogenetic target in asthma therapy. At present, special attention is focused on natural (polyunsaturated fatty acids (PUFAs), endocannabinoids, and eicosanoids) and synthetic (fibrates, thiazolidinediones) PPAR ligands and the study of signaling mechanisms involved in the implementation of their anti-inflammatory effects in asthma. This review summarizes current views on the structure and function of PPARs, as well as their participation in the pathogenesis of chronic inflammation in asthma. The potential use of PPAR ligands as therapeutic agents for treating asthma is under discussion.

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Regulation of peroxisome proliferator‐activated receptors (PPAR) α and ‐γ of rat brain astrocytes in the course of activation by toll‐like receptor agonists

Cited by 47 publications

References 52 publications

PPARβ/δ‐agonist GW0742 ameliorates dysfunction in fatty acid oxidation in PSEN1ΔE9 astrocytes

PPARβ/δ‐agonist GW0742 ameliorates dysfunction in fatty acid oxidation in PSEN1ΔE9 astrocytes

Interactions of TLR4 and PPARγ, Dependent on AMPK Signalling Pathway Contribute to Anti-Inflammatory Effects of Vaccariae Hypaphorine in Endothelial Cells

Peroxisome Proliferator-Activated Receptors as a Therapeutic Target in Asthma

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