Natural products as modulators of the nuclear receptors and metabolic sensors LXR, FXR and RXR

Hiebl, Verena; Ladurner, Angela; Latkolik, Simone; Dirsch, Verena M.

doi:10.1016/j.biotechadv.2018.03.003

Cited by 95 publications

(84 citation statements)

References 400 publications

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“…Further molecular studies were carried out to test the potential protection mechanism of quercetin toward BAs homeostasis and lipid metabolism in T2DM‐induced NAFLD. In recent years, studies have shown that FXR not only regulated BA metabolism but also played an important role in the metabolism of carbohydrates, lipids, and hydrocarbons (Hiebl, Ladurner, Latkolik, & Dirsch, ; Y. D. Wang, Chen, Moore, & Huang, ). A recent study shows that serum and liver triglyceride levels could be reduced by the treatment of FXR agonists in db / db mice (Y. Liu et al, ).…”

Section: Discussionmentioning

confidence: 99%

Quercetin improves nonalcoholic fatty liver by ameliorating inflammation, oxidative stress, and lipid metabolism in db/db mice

Yang

Cai

et al. 2019

Phytotherapy Research

145

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Multiphase pathological processes involve in Type 2 diabetes (T2DM)‐induced nonalcoholic fatty liver disease (NAFLD). However, the therapies are quite limited. In the present study, the hepatoprotective effects and underlying mechanisms of quercetin in T2DM‐induced NAFLD were investigated. T2DM‐induced NAFLD and quercetin treatment models were established in vivo and in vitro. The results revealed that quercetin alleviated serum transaminase levels and markedly reduced T2DM‐induced histological alterations of livers. Additionally, quercetin restored superoxide dismutase, catalase, and glutathione content in livers. Not only that, quercetin markedly attenuated T2DM‐induced production of interleukin 1 beta, interleukin 6, and TNF‐α. Accompanied by the restoration of the increased serum total bile acid (p = .0001) and the decreased liver total bile acid (p = .0005), quercetin could reduce lipid accumulation in the liver of db/db mice. Further mechanism studies showed that farnesoid X receptor 1/Takeda G‐protein‐coupled receptor 5 signaling pathways was involved in quercetin regulation of lipid metabolism in T2DM‐induced NAFLD. In high D‐glucose and free fatty acid cocultured HepG2 cells model, quercetin eliminated lipid droplets and restored the upregulated total cholesterol and triglyceride levels. Similar to the findings in mice, quercetin could also activate farnesoid X receptor 1/Takeda G‐protein‐coupled receptor 5 signaling pathway. These findings suggested that quercetin might be a potentially effective drug for the treatment of T2DM‐induced NAFLD.

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Section: Discussionmentioning

confidence: 99%

Quercetin improves nonalcoholic fatty liver by ameliorating inflammation, oxidative stress, and lipid metabolism in db/db mice

Yang

Cai

et al. 2019

Phytotherapy Research

145

View full text Add to dashboard Cite

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“…5E, Supplemental Table 5). The LXR/RXR pathway has been reported to increase cholesterol efflux and repress TLR4-induced genes (Hiebl et al, 2018), but also to promote inflammasome activation in microglia (Jang et al, 2016). However, inhibition of classical pro-inflammatory pathways, such as the acute phase response and NFκB signaling, as well as of TREM1 signaling, that sustains inflammation (Owens et al, 2017), was also predicted ( Fig.…”

Section: Gene Expression Changes In Csf1r +/-Microglia Suggest a Malamentioning

confidence: 93%

Microglial homeostasis requires balanced CSF-1/CSF-2 receptor signaling

Chiţu

Biundo

Shlager

et al. 2019

Preprint

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CSF-1R haploinsufficiency causes adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP). Previous studies in the Csf1r +/mouse model of ALSP hypothesized a central role of elevated cerebral Csf2 expression. Here we show that monoallelic deletion of Csf2 rescues most behavioral deficits and histopathological changes in Csf1r +/mice by preventing microgliosis and eliminating most microglial transcriptomic alterations, including those indicative of oxidative stress and demyelination. We also show elevation of Csf2 transcripts and of several CSF-2 downstream targets in the brains of ALSP patients, demonstrating that the mechanisms identified in the mouse model are functional in man. Our data provide new insights into the mechanisms underlying ALSP. Since both increased CSF2 levels and decreased microglial Csf1r expression have also been reported in Alzheimer's disease and multiple sclerosis, we suggest that the unbalanced CSF-1R/CSF-2 signaling we describe in the present study may contribute to the pathogenesis of other neurodegenerative conditions. Abbreviations: CSF-1 RColony stimulating factor-1 receptor CSF-2Colony stimulating factor-2 ALSP Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia Highlights• ALSP is a CSF1R-deficiency dementia associated with increased CSF2 expression • In Csf1r+/-ALSP mice CSF-2 promotes microgliosis by direct signaling in microglia • Targeting Csf2 improves cognition, myelination and normalizes microglial function • CSF-2 is a therapeutic target in ALSP

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“…Based on in silico and in vivo studies it had been previously reported that norbixin is a PPAR-g agonist such as pioglitazone (25). However, NRs responsiveness in response to ligands depends on the specific cellular context and experimental settings (16,19). Indeed, by contrast, it has been shown that norbixin at 20 µM did not induce PPAR-g transactivation in 3T3-L1 adipocytes (26).…”

Section: Discussionmentioning

confidence: 99%

“…Due to the permissive nature of PPARs heterodimers (16,19), A2E-induced transactivation of PPAR/RXR heterodimers could result from direct binding of A2E to PPARs, RXR-a or both. Moreover, it has been shown that an agonist ligand of RXRs/RXRs homodimers can also induce the transactivation of PPARs by direct binding on the PPARs response elements (36).…”

Section: Discussionmentioning

confidence: 99%

“…Alternatively, RARs/RXRs heterodimers transactivation could be induced by a bi-specific agonist. By contrast, in the context of permissive heterodimers such as PPARs/RXRs or liver X receptors (LXRs)/RXRs, binding of an agonist of the specific NR partner or of an agonist of RXRs alone is sufficient to transactivate the NR partner (16,19). RARs, RXRs and PPARs are known to regulate a wide spectrum of biological pathways ranging from metabolism, cell death, inflammation and angiogenesis (14) that are involved in AMD pathogenesis (20)(21)(22).…”

Section: Introductionmentioning

confidence: 99%

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A2E induces the transactivation of RARs, PPARs and RXRs and its effects are counteracted by norbixin in retinal pigment epithelium cells in vitro

Fontaine

Fournié

Monteiro

et al. 2020

Preprint

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N-retinylidene-N-retinylethanolamine (A2E) plays a central role in age-related macular degeneration (AMD) by inducing apoptosis, angiogenesis and inflammation. It has been proposed that A2E effects are mediated at least partly via the retinoic acid receptor (RAR)-a. Here we show that A2E binds and transactivates not only RARs, but also peroxisome proliferator-activated receptors (PPARs) and retinoid X receptors (RXRs). Norbixin, which protects retinal pigment epithelium (RPE) cells against apoptosis induced by combined blue light illumination and A2E exposure, is also a ligand of these nuclear receptors (NRs) but does not induce their transactivation. Norbixin inhibits RXRs andPPARs but enhances RARs transactivation induced by A2E. Norbixin also inhibits PPAR-g transactivation induced by its high affinity ligand troglitazone. activator protein 1 (AP-1) transactivation, and the mRNA expression of the inflammatory interleukins (IL) 6 and 8 and of vascular endothelial growth factor (VEGF) that are enhanced by A2E. By contrast, norbixin increases matrix metalloproteinase 9 (MMP9) and C-C motif chemokine ligand 2 (CCL2) mRNA expression but has neither effect on extracellular signal-regulated kinase (ERK) phosphorylation, nor on IL-18 mRNA Norbixin modulates NRs activation by A2E in RPE cells 2 expression in response to A2E. Altogether, we show for the first time that A2E deleterious biological effects appear to be mediated through RARs, PPARs and RXRs. Moreover, we report that the modulation of these NRs by norbixin may open new avenues for the treatment of AMD. Photoprotection of RPE cells by norbixin correlates with maintained levels of the antiapoptotic B-cell lymphoma 2 (Bcl2) protein. Moreover, norbixin reduces protein kinase B (AKT) phosphorylation, NF-kB and

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Natural products as modulators of the nuclear receptors and metabolic sensors LXR, FXR and RXR

Cited by 95 publications

References 400 publications

Quercetin improves nonalcoholic fatty liver by ameliorating inflammation, oxidative stress, and lipid metabolism in db/db mice

Quercetin improves nonalcoholic fatty liver by ameliorating inflammation, oxidative stress, and lipid metabolism in db/db mice

Microglial homeostasis requires balanced CSF-1/CSF-2 receptor signaling

A2E induces the transactivation of RARs, PPARs and RXRs and its effects are counteracted by norbixin in retinal pigment epithelium cells in vitro

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