Marine Bile Natural Products as Agonists of the TGR5 Receptor

Halkias, Christopher; Darby, William; Feltis, Bryce; McIntyre, Peter; Macrides, Theodore A.; Wright, Paul

doi:10.1021/acs.jnatprod.0c01327

Cited by 10 publications

(7 citation statements)

References 40 publications

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“…Consistent with our findings, the regulatory effect of TGR5 on PKA has been confirmed by literature (Hu et al, 2021;Jin et al, 2021). Interestingly, many documents showed that TGR5 is involved in the regulation of intracellular Ca 2+ levels (Maczewsky et al, 2019;Bensalem et al, 2020;Halkias et al, 2021). Our present research found that TGR5 can stabilize endothelial cell mitochondrial dynamics and protect endothelial cells from HG damage.…”

Section: Discussionsupporting

confidence: 92%

TGR5 Activation Ameliorates Mitochondrial Homeostasis via Regulating the PKCδ/Drp1-HK2 Signaling in Diabetic Retinopathy

Zhang

Zhu

Zheng

et al. 2022

Front. Cell Dev. Biol.

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Background: Diabetic retinopathy (DR) is one of the most important microvascular diseases of diabetes. Our previous research demonstrated that bile acid G-protein-coupled membrane receptor (TGR5), a novel cell membrane receptor of bile acid, ameliorates the vascular endothelial cell dysfunction in DR. However, the precise mechanism leading to this alteration remains unknown. Thus, the mechanism of TGR5 in the progress of DR should be urgently explored.Methods: In this study, we established high glucose (HG)-induced human retinal vascular endothelial cells (RMECs) and streptozotocin-induced DR rat in vitro and in vivo. The expression of TGR5 was interfered through the specific agonist or siRNA to study the effect of TGR5 on the function of endothelial cell in vitro. Western blot, immunofluorescence and fluorescent probes were used to explore how TGR5 regulated mitochondrial homeostasis and related molecular mechanism. The adeno-associated virus serotype 8-shTGR5 (AAV8-shTGR5) was performed to evaluate retinal dysfunction in vivo and further confirm the role of TGR5 in DR by HE staining, TUNEL staining, PAS staining and Evans Blue dye.Results: We found that TGR5 activation alleviated HG-induced endothelial cell apoptosis by improving mitochondrial homeostasis. Additionally, TGR5 signaling reduced mitochondrial fission by suppressing the Ca2+-PKCδ/Drp1 signaling and enhanced mitophagy through the upregulation of the PINK1/Parkin signaling pathway. Furthermore, our result indicated that Drp1 inhibited mitophagy by facilitating the hexokinase (HK) 2 separation from the mitochondria and HK2-PINK1/Parkin signaling. In vivo, intraretinal microvascular abnormalities, including retinal vascular leakage, acellular capillaries and apoptosis, were poor in AAV8-shTGR5-treated group under DR, but this effect was reversed by pretreatment with the mitochondrial fission inhibitor Mdivi-1 or autophagy agonist Rapamycin.Conclusion: Overall, our findings indicated that TGR5 inhibited mitochondrial fission and enhanced mitophagy in RMECs by regulating the PKCδ/Drp1-HK2 signaling pathway. These results revealed the molecular mechanisms underlying the protective effects of TGR5 and suggested that activation of TGR5 might be a potential therapeutic strategy for DR.

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Section: Discussionsupporting

confidence: 92%

TGR5 Activation Ameliorates Mitochondrial Homeostasis via Regulating the PKCδ/Drp1-HK2 Signaling in Diabetic Retinopathy

Zhang

Zhu

Zheng

et al. 2022

Front. Cell Dev. Biol.

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“…The stronger neurotrophic effects of DCA relative to CDCA are consistent with our findings that TGR5 signaling appears to mediate neurite outgrowth. DCA is a known activator of TGR5 [ 50 , 51 ], as is CDCA [ 52 , 53 ], though DCA is a more potent agonist of TGR5 than CDCA, which is reversed, i.e., CDCA is greater than DCA, for FXR agonism [ 54 ]. Of relevance to ALS, TCDCA is able to bind to the TGR5 receptor and activate it [ 55 , 56 ].…”

Section: Discussionmentioning

confidence: 99%

Bile Acids Induce Neurite Outgrowth in Nsc-34 Cells via TGR5 and a Distinct Transcriptional Profile

Ackerman

Gerhard

2023

Pharmaceuticals

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Increasing evidence supports a neuroprotective role for bile acids in major neurodegenerative disorders. We studied major human bile acids as signaling molecules for their two cellular receptors, farnesoid X receptor (FXR or NR1H4) and G protein-coupled bile acid receptor 1 (GPBAR1 or TGR5), as potential neurotrophic agents. Using quantitative image analysis, we found that 20 μM deoxycholic acid (DCA) could induce neurite outgrowth in NSC-34 cells that was comparable to the neurotrophic effects of the culture control 1 μM retinoic acid (RA), with lesser effects observed for chenodexoycholic acid (CDCA) at 20 μM, and similar though less robust neurite outgrowth in SH-SY5Y cells. Using chemical agonists and antagonists of FXR, LXR, and TGR5, we found that TGR5 agonism was comparable to DCA stimulation and stronger than RA, and that neither FXR nor liver X receptor (LXR) inhibition could block bile acid-induced neurite growth. RNA sequencing identified a core set of genes whose expression was regulated by DCA, CDCA, and RA. Our data suggest that bile acid signaling through TGR5 may be a targetable pathway to stimulate neurite outgrowth.

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“…The stronger neurotrophic effects of DCA relative to CDCA is consistent with our ndings that TGR5 signaling appears to mediate the neurite outgrowth. DCA is a known activator of TGR5 [41,42] as is CDCA [43,44], though DCA is a more potent agonist of TGR5 than CDCA, which is reversed, i.e., CDCA greater than DCA, for FXR agonism [45]. Of relevance to ALS, TCDCA is able to bind to the TGR5 receptor and activate it [46,47].…”

Section: Discussionmentioning

confidence: 99%

Bile acids induce neurite outgrowth in NSC-34 cells via TGR5 and a distinct transcriptional profile

Gerhard

Ackerman

2022

Preprint

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Bile acids have recently emerged as potential neuroprotective agents that may modulate neurodegeneration. Most studies have focused on the single bile acid tauroursodeoxycholic acid (TUDCA) and its role as an anti-apoptotic agent. We studied other bile acids as signaling molecules for their two cellular receptors, farnesoid X receptor (FXR or NR1H4) and G protein-coupled bile acid receptor 1 (GPBAR1 or TGR5), and for liver X receptor (LXR), as potential neurotrophic agents. We used two in vitro model systems to identify the effects of bile acids and related pharmacological agents on neurite outgrowth using quantitative image analysis. We also identified early effects on gene expression using RNA sequencing analysis. We found that 20 uM deoxycholic acid (DCA) could induce neurite outgrowth in NSC-34 cells that was comparable to the neurotrophic effects of the culture control 1 uM retinoic acid (RA) with similar, but slightly less robust effects observed for chenodexoycholic acid (CDCA) at 20 uM and in SH-SY5Y cells. Using chemical agonists and antagonists of FXR, LXR, and TGR5, TGR5 agonism was comparable to DCA stimulation, stronger than RA, and neither FXR nor LXR inhibition could block bile acid-induced neurite growth. RNA sequencing identified a core set of genes whose expression was regulated by DCA, CDCA, and RA. Our data suggest that bile acid signaling through TGR5 may be a targetable pathway to stimulate neurite outgrowth.

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Marine Bile Natural Products as Agonists of the TGR5 Receptor

Cited by 10 publications

References 40 publications

TGR5 Activation Ameliorates Mitochondrial Homeostasis via Regulating the PKCδ/Drp1-HK2 Signaling in Diabetic Retinopathy

TGR5 Activation Ameliorates Mitochondrial Homeostasis via Regulating the PKCδ/Drp1-HK2 Signaling in Diabetic Retinopathy

Bile Acids Induce Neurite Outgrowth in Nsc-34 Cells via TGR5 and a Distinct Transcriptional Profile

Bile acids induce neurite outgrowth in NSC-34 cells via TGR5 and a distinct transcriptional profile

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