Relevant bibliographies by topics / TGR5

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  2. Dissertations / Theses
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  4. Book chapters
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Academic literature on the topic 'TGR5'

Author: Grafiati
Published: 4 June 2021
Last updated: 10 March 2023

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Journal articles on the topic "TGR5"

1

Rao, Jianhua, Chao Yang, Shikun Yang, Hao Lu, Yuanchang Hu, Ling Lu, Feng Cheng, and Xuehao Wang. "Deficiency of TGR5 exacerbates immune-mediated cholestatic hepatic injury by stabilizing the β-catenin destruction complex." International Immunology 32, no. 5 (January 13, 2020): 321–34. http://dx.doi.org/10.1093/intimm/dxaa002.

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Abstract Intrahepatic cholestasis induced by drug toxicity may cause cholestatic hepatic injury (CHI) leading to liver fibrosis and cirrhosis. The G protein-coupled bile acid receptor 1 (TGR5) is a membrane receptor with well-known roles in the regulation of glucose metabolism and energy homeostasis. However, the role and mechanism of TGR5 in the context of inflammation during CHI remains unclear. Wild-type (WT) and TGR5 knockout (TGR5−/−) mice with CHI induced by bile duct ligation (BDL) were involved in vivo, and WT and TGR5−/− bone marrow-derived macrophages (BMDMs) were used in vitro. TGR5 deficiency significantly exacerbated BDL-induced liver injury, inflammatory responses and hepatic fibrosis compared with WT mice in vivo. TGR5−/− macrophages were more susceptible to lipopolysaccharide (LPS) stimulation than WT macrophages. TGR5 activation by its ligand suppressed LPS-induced pro-inflammatory responses in WT but not TGR5−/− BMDMs. Notably, expression of β-catenin was effectively inhibited by TGR5 deficiency. Furthermore, TGR5 directly interacted with Gsk3β to repress the interaction between Gsk3β and β-catenin, thus disrupting the β-catenin destruction complex. The pro-inflammatory nature of TGR5-knockout was almost abolished by lentivirus-mediated β-catenin overexpression in BMDMs. BMDM migration in vitro was accelerated under TGR5-deficient conditions or supernatant from LPS-stimulated TGR5−/− BMDMs. From a therapeutic perspective, TGR5−/− BMDM administration aggravated BDL-induced CHI, which was effectively rescued by β-catenin overexpression. Our findings reveal that TGR5 plays a crucial role as a novel regulator of immune-mediated CHI by destabilizing the β-catenin destruction complex, with therapeutic implications for the management of human CHI.
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2

Gillard, Justine, Corinne Picalausa, Christoph Ullmer, Luciano Adorini, Bart Staels, Anne Tailleux, and Isabelle A. Leclercq. "Enterohepatic Takeda G-Protein Coupled Receptor 5 Agonism in Metabolic Dysfunction-Associated Fatty Liver Disease and Related Glucose Dysmetabolism." Nutrients 14, no. 13 (June 29, 2022): 2707. http://dx.doi.org/10.3390/nu14132707.

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Metabolic dysfunction-associated fatty liver disease (MAFLD) is a major health concern with no approved pharmacological therapies. Molecules developed to activate the bile acid-receptor TGR5 regulate pathways involved in MALFD pathogenesis, but the therapeutic value of TGR5 activation on the active form of MAFLD, non-alcoholic steatohepatitis (NASH), still needs to be evaluated. As TGR5 agonism is low in MAFLD, we used strategies to promote the production of endogenous TGR5 ligands or administered pharmacological TGR5 agonists, INT-777 and RO5527239, to study the effect of TGR5 activation on liver and metabolic diseases in high-fat diet-fed foz/foz mice. Although described in the literature, treatment with fexaramine, an intestine-restricted FXR agonist, did not raise the concentrations of TGR5 ligands nor modulate TGR5 signaling and, accordingly, did not improve dysmetabolic status. INT-777 and RO5527239 directly activated TGR5. INT-777 only increased the TGR5 activation capacity of the portal blood; RO5527239 also amplified the TGR5 activation capacity of systemic blood. Both molecules improved glucose tolerance. In spite of the TGR5 activation capacity, INT-777, but not RO5527239, reduced liver disease severity. In conclusion, TGR5 activation in enterohepatic, rather than in peripheral, tissues has beneficial effects on glucose tolerance and MAFLD.
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Holter, Marlena M., Margot K. Chirikjian, Viraj N. Govani, and Bethany P. Cummings. "TGR5 Signaling in Hepatic Metabolic Health." Nutrients 12, no. 9 (August 26, 2020): 2598. http://dx.doi.org/10.3390/nu12092598.

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TGR5 is a G protein-coupled bile acid receptor that is increasingly recognized as a key regulator of glucose homeostasis. While the role of TGR5 signaling in immune cells, adipocytes and enteroendocrine L cells in metabolic regulation has been well described and extensively reviewed, the impact of TGR5-mediated effects on hepatic physiology and pathophysiology in metabolic regulation has received less attention. Recent studies suggest that TGR5 signaling contributes to improvements in hepatic insulin signaling and decreased hepatic inflammation, as well as metabolically beneficial improvements in bile acid profile. Additionally, TGR5 signaling has been associated with reduced hepatic steatosis and liver fibrosis, and improved liver function. Despite the beneficial effects of TGR5 signaling on metabolic health, TGR5-mediated gallstone formation and gallbladder filling complicate therapeutic targeting of TGR5 signaling. To this end, there is a growing need to identify cell type-specific effects of hepatic TGR5 signaling to begin to identify and target the downstream effectors of TGR5 signaling. Herein, we describe and integrate recent advances in our understanding of the impact of TGR5 signaling on liver physiology and how its effects on the liver integrate more broadly with whole body glucose regulation.
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Merlen, Grégory, Nicolas Kahale, Jose Ursic-Bedoya, Valeska Bidault-Jourdainne, Hayat Simerabet, Isabelle Doignon, Zahra Tanfin, et al. "TGR5-dependent hepatoprotection through the regulation of biliary epithelium barrier function." Gut 69, no. 1 (February 5, 2019): 146–57. http://dx.doi.org/10.1136/gutjnl-2018-316975.

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ObjectiveWe explored the hypothesis that TGR5, the bile acid (BA) G-protein-coupled receptor highly expressed in biliary epithelial cells, protects the liver against BA overload through the regulation of biliary epithelium permeability.DesignExperiments were performed under basal and TGR5 agonist treatment. In vitro transepithelial electric resistance (TER) and FITC-dextran diffusion were measured in different cell lines. In vivo FITC-dextran was injected in the gallbladder (GB) lumen and traced in plasma. Tight junction proteins and TGR5-induced signalling were investigated in vitro and in vivo (wild-type [WT] and TGR5-KO livers and GB). WT and TGR5-KO mice were submitted to bile duct ligation or alpha-naphtylisothiocyanate intoxication under vehicle or TGR5 agonist treatment, and liver injury was studied.ResultsIn vitro TGR5 stimulation increased TER and reduced paracellular permeability for dextran. In vivo dextran diffusion after GB injection was increased in TGR5-knock-out (KO) as compared with WT mice and decreased on TGR5 stimulation. In TGR5-KO bile ducts and GB, junctional adhesion molecule A (JAM-A) was hypophosphorylated and selectively downregulated among TJP analysed. TGR5 stimulation induced JAM-A phosphorylation and stabilisation both in vitro and in vivo, associated with protein kinase C-ζ activation. TGR5 agonist-induced TER increase as well as JAM-A protein stabilisation was dependent on JAM-A Ser285 phosphorylation. TGR5 agonist-treated mice were protected from cholestasis-induced liver injury, and this protection was significantly impaired in JAM-A-KO mice.ConclusionThe BA receptor TGR5 regulates biliary epithelial barrier function in vitro and in vivo through an impact on JAM-A expression and phosphorylation, thereby protecting liver parenchyma against bile leakage.
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Li, Suchun, Miaojuan Qiu, Yonglun Kong, Xiaoduo Zhao, Hyo-Jung Choi, Maria Reich, Brady H. Bunkelman, et al. "Bile Acid G Protein-Coupled Membrane Receptor TGR5 Modulates Aquaporin 2–Mediated Water Homeostasis." Journal of the American Society of Nephrology 29, no. 11 (October 10, 2018): 2658–70. http://dx.doi.org/10.1681/asn.2018030271.

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BackgroundThe bile acid-activated receptors, including the membrane G protein–coupled receptor TGR5 and nuclear farnesoid X receptor (FXR), have roles in kidney diseases. In this study, we investigated the role of TGR5 in renal water handling and the underlying molecular mechanisms.MethodsWe used tubule suspensions of inner medullary collecting duct (IMCD) cells from rat kidneys to investigate the effect of TGR5 signaling on aquaporin-2 (AQP2) expression, and examined the in vivo effects of TGR5 in mice with lithium-induced nephrogenic diabetes insipidus (NDI) and Tgr5 knockout (Tgr5−/−) mice.ResultsActivation of TGR5 by lithocholic acid (LCA), an endogenous TGR5 ligand, or INT-777, a synthetic TGR5-specific agonist, induced AQP2 expression and intracellular trafficking in rat IMCD cells via a cAMP-protein kinase A signaling pathway. In mice with NDI, dietary supplementation with LCA markedly decreased urine output and increased urine osmolality, which was associated with significantly upregulated AQP2 expression in the kidney inner medulla. Supplementation with endogenous FXR agonist had no effect. In primary IMCD suspensions from lithium-treated rats, treatment with INT-767 (FXR and TGR5 dual agonist) or INT-777, but not INT-747 (FXR agonist), increased AQP2 expression. Tgr5−/− mice exhibited an attenuated ability to concentrate urine in response to dehydration, which was associated with decreased AQP2 expression in the kidney inner medulla. In lithium-treated Tgr5−/− mice, LCA treatment failed to prevent reduction of AQP2 expression.ConclusionsTGR5 stimulation increases renal AQP2 expression and improves impaired urinary concentration in lithium-induced NDI. TGR5 is thus involved in regulating water metabolism in the kidney.
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Willis, Kent A., Charles K. Gomes, Prahlad Rao, Dejan Micic, E. Richard Moran, Erin Stephenson, Michelle Puchowicz, et al. "TGR5 signaling mitigates parenteral nutrition-associated liver disease." American Journal of Physiology-Gastrointestinal and Liver Physiology 318, no. 2 (February 1, 2020): G322—G335. http://dx.doi.org/10.1152/ajpgi.00216.2019.

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Bile acid receptors regulate the metabolic and immune functions of circulating enterohepatic bile acids. This process is disrupted by administration of parenteral nutrition (PN), which may induce progressive hepatic injury for unclear reasons, especially in the newborn, leading to PN-associated liver disease. To explore the role of bile acid signaling on neonatal hepatic function, we initially observed that Takeda G protein receptor 5 (TGR5)-specific bile acids were negatively correlated with worsening clinical disease markers in the plasma of human newborns with prolonged PN exposure. To test our resulting hypothesis that TGR5 regulates critical liver functions to PN exposure, we used TGR5 receptor deficient mice (TGR5−/−). We observed PN significantly increased liver weight, cholestasis, and serum hepatic stress enzymes in TGR5−/− mice compared with controls. Mechanistically, PN reduced bile acid synthesis genes in TGR5−/−. Serum bile acid composition revealed that PN increased unconjugated primary bile acids and secondary bile acids in TGR5−/− mice, while increasing conjugated primary bile acid levels in TGR5-competent mice. Simultaneously, PN elevated hepatic IL-6 expression and infiltrating macrophages in TGR5−/− mice. However, the gut microbiota of TGR5−/− mice compared with WT mice following PN administration displayed highly elevated levels of Bacteroides and Parabacteroides, and possibly responsible for the elevated levels of secondary bile acids in TGR5−/− animals. Intestinal bile acid transporters expression was unchanged. Collectively, this suggests TGR5 signaling specifically regulates fundamental aspects of liver bile acid homeostasis during exposure to PN. Loss of TGR5 is associated with biochemical evidence of cholestasis in both humans and mice on PN. NEW & NOTEWORTHY Parenteral nutrition is associated with deleterious metabolic outcomes in patients with prolonged exposure. Here, we demonstrate that accelerated cholestasis and parental nutrition-associated liver disease (PNALD) may be associated with deficiency of Takeda G protein receptor 5 (TGR5) signaling. The microbiome is responsible for production of secondary bile acids that signal through TGR5. Therefore, collectively, these data support the hypothesis that a lack of established microbiome in early life or under prolonged parenteral nutrition may underpin disease development and PNALD.
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Reich, Maria, Caroline Klindt, Kathleen Deutschmann, Lina Spomer, Dieter Häussinger, and Verena Keitel. "Role of the G Protein-Coupled Bile Acid Receptor TGR5 in Liver Damage." Digestive Diseases 35, no. 3 (2017): 235–40. http://dx.doi.org/10.1159/000450917.

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Background: TGR5 (G protein-coupled bile acid receptor 1, M-Bar) is a G protein-coupled cell surface receptor responsive to bile acids (BA) and different steroid hormones. TGR5 mRNA is detected almost ubiquitious in human and rodent tissues with a very high expression in gallbladder, liver and intestine. In liver, TGR5 is found in sinusoidal endothelial cells, Kupffer cells and cholangiocytes. Activation of TGR5 triggers an elevation of intracellular cyclic AMP and further downstream signalling. Key Messages: TGR5 exerts anti-inflammatory effects, protects cholangiocytes from BA-induced toxicity, promotes cholangiocyte secretion and proliferation and reduces portal perfusion pressure. Furthermore, TGR5 mediates gallbladder filling. TGR5 knockout mice have a smaller BA pool size with altered composition and develop more severe liver injury after BA feeding, common bile duct ligation or injection of lipopolysaccharide. The absence of TGR5 also reduces the proliferative and regenerative capacity after partial hepatectomy or liver damage. Stimulation of TGR5 signalling can improve steatohepatitis, portal hypertension and hepatic inflammation in rodent models of liver damage. However, TGR5 activation also promotes the proliferation of cystic and malignant-transformed cholangiocytes. Conclusions: TGR5 plays an important role in the protection of the liver from BA toxicity under cholestatic conditions. Stimulation of the receptor prevents excessive liver damage in rodent models of cholestasis, steatohepatitis, liver fibrosis and inflammation and also promotes liver regeneration. However, the activation of TGR5-dependent signalling may also trigger proliferation and apoptosis resistance of cystic cholangiocytes and malignantly transformed cholangiocytes, thus promoting cyst growth in polycystic liver disease or progression of cholangiocarcinoma. Depending on the type of liver disease stimulation as well as inhibition of TGR5, signalling may present a useful therapeutic approach.
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Cao, Weibiao, Wei Tian, Jie Hong, Dan Li, Rosemarie Tavares, Lelia Noble, Steven F. Moss, and Murray B. Resnick. "Expression of bile acid receptor TGR5 in gastric adenocarcinoma." American Journal of Physiology-Gastrointestinal and Liver Physiology 304, no. 4 (February 15, 2013): G322—G327. http://dx.doi.org/10.1152/ajpgi.00263.2012.

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Bile reflux is a risk factor in the development of intestinal metaplasia in the stomach and is believed to function as an initiator of gastric carcinogenesis. However, whether the G protein-coupled bile acid receptor TGR5 is expressed in this tumor is not known. In this study, we determined the expression of TGR5 in gastric adenocarcinoma and examined the role of TGR5 in cell proliferation. Strong TGR5 staining was present in 12% of cases of intestinal metaplasia but in no cases of normal gastric epithelium ( P < 0.01). Moderate to strong TGR5 membranous and cytoplasmic staining was present in 52% of the intestinal but in only 25% of the diffuse subtype of adenocarcinomas ( P < 0.001). Kaplan-Meier univariate survival analysis revealed that moderate to strong TGR5 staining was associated with decreased patient survival ( P < 0.05). Treatment with taurodeoxycholic acid (TDCA, a bile acid) significantly increased thymidine incorporation in the AGS gastric adenocarcinoma cell line, suggesting that bile acids may increase cell proliferation. This increase was significantly decreased by knockdown of TGR5 with TGR5 small-interfering RNA (siRNA). In addition, overexpression of TGR5 significantly enhanced TDCA-induced increases in thymidine incorporation. TGR5 is coupled with Gqα and Gαi-3 proteins. TDCA-induced increase in thymidine incorporation was significantly decreased by knockdown of Gqα and Gαi-3 with their siRNAs. We conclude that TGR5 is overexpressed in most gastric intestinal-type adenocarcinomas, and moderate to strong TGR5 staining is associated with decreased patient survival in all gastric adenocarcinomas. Bile acids increase cell proliferation via activation of TGR5 receptors and Gqα and Gαi-3 proteins.
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Yang, Haojun, Hanyang Liu, YuWen Jiao, and Jun Qian. "Roux-en-Y Gastrointestinal Bypass Promotes Activation of TGR5 and Peptide YY." Endocrine, Metabolic & Immune Disorders - Drug Targets 20, no. 8 (October 15, 2020): 1262–67. http://dx.doi.org/10.2174/1871530320666200628024500.

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Background: G protein-coupled bile acid receptor (TGR5) is involved in a number of metabolic diseases. The aim of this study was to identify the role of TGR5 after Roux-en-Y gastric bypass (GBP). Methods: Wild type and TGR5 knockout mice (tgr5-/-) were fed a high-fat diet (HFD) to establish the obesity model. GBP was performed. The changes in body weight and food intake were measured. The levels of TGR5 and peptide YY (PYY) were evaluated by RT-PCR, Western blot, and ELISA. Moreover, the L-cells were separated from wild type and tgr5-/- mice. The levels of PYY in L-cells were evaluated by ELISA. Results: The body weights were significantly decreased after GBP in wild type mice (p<0.05), but not tgr5-/- mice (p>0.05). Food intake was reduced after GBP in wild type mice, but also not significantly affected in tgr5-/- mice (p>0.05). The levels of PYY were significantly increased after GBP compared with the sham group (p<0.05); however, in tgr5-/- mice the expression of PYY was not significantly affected (p>0.05). After INT-777 stimulation in L-cells obtained from murine intestines, the levels of PYY were significantly increased in L-cells tgr5+/+ (p<0.05). Conclusion: Our study suggests that GBP up-regulated the expression of TGR5 in murine intestines, and increased the levels of PYY, which further reduced food intake and decreased the body weight.
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Jourdainne, Valeska, Noémie Péan, Isabelle Doignon, Lydie Humbert, Dominique Rainteau, and Thierry Tordjmann. "The Bile Acid Receptor TGR5 and Liver Regeneration." Digestive Diseases 33, no. 3 (2015): 319–26. http://dx.doi.org/10.1159/000371668.

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Background: Most of the literature on the bile acid (BA) membrane receptor TGR5 is dedicated to its potential role in the metabolic syndrome, through its regulatory impact on energy expenditure, insulin and GLP-1 secretion, and inflammatory processes. While the receptor was cloned in 2002, very little data are available on TGR5 functions in the normal and diseased liver. However, TGR5 is highly expressed in Kupffer cells and liver endothelial cells, and is particularly enriched in the biliary tract [cholangiocytes and gallbladder (GB) smooth muscle cells]. We recently demonstrated that TGR5 has a crucial protective impact on the liver in case of BA overload, including after partial hepatectomy. Key Messages: TGR5-KO mice after PH exhibited periportal bile infarcts, excessive hepatic inflammation and defective adaptation of biliary composition (bicarbonate and chloride). Most importantly, TGR5-KO mice had a more hydrophobic BA pool, with more secondary BA than WT animals, suggesting that TGR5-KO bile may be harmful for the liver, mainly in situations of BA overload. As GB is both the tissue displaying the highest level of TGR5 expression and a crucial physiological site for the regulation of BA pool hydrophobicity by reducing secondary BA, we investigated whether TGR5 may control BA pool composition through an impact on GB. Preliminary data suggest that in the absence of TGR5, reduced GB filling dampens the cholecystohepatic shunt, resulting in more secondary BA, more hydrophobic BA pool and extensive liver injury in case of BA overload. Conclusions: In the setting of BA overload, TGR5 is protective of the liver through the regulation of not only secretory and inflammatory processes, but also through the control of BA pool composition, at least in part by targeting the GB. Thereby, TGR5 appears to be crucial for protecting the regenerating liver from BA overload.
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Dissertations / Theses on the topic "TGR5"

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Sato, Hiroyuki. "Identification and biological validation of natural TGR5 agonists." Université Louis Pasteur (Strasbourg) (1971-2008), 2007. http://www.theses.fr/2007STR13232.

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Les acides biliaires agissent comme des molécules anti-obésité, en augmentant la dépense énergétique via l’activation d’un récepteur membranaire pour les acides biliaires, le TGR5. Dans ce travail de thèse, nous avons étudié extensivement différents agonistes pour le TGR5, ainsi que leurs propriétés pharmacologiques, en particulier pour leur utilisation potentielle dans le traitement des maladies métaboliques. Dans la première étude, nous avons établi les relations structure / activité sur le TGR5 pour plus de 80 acides biliaires (et dérivés) naturels. Ce travail a permis d’identifier les caractéristiques structurales que devaient présenter les acides biliaires pour activer le TGR5, et en outre a permis l’identification de plusieurs agonistes puissants pour le TGR5. Dans une deuxième étude, nous nous sommes intéressés à un phytostérol, la gugulstérone (GS), connue pour ses effets régulateurs sur le métabolisme. Nous avons montré que GS est également un puissant agoniste du TGR5. Biologiquement, GS active Dio2 et augmente la consommation d’oxygène chez l’animal et dans des modèles cellulaires. Dans la troisième étude, nous avons criblés des extraits de plantes afin d’identifier d’autres agonistes du TGR5. Ce criblage a permis d’identifier 21 plantes activant le TGR5 dont une pour laquelle une sélection bio-guidée nous a permis d'identifier une molécule originale agoniste du TGR5 dont la structure a été confirmé par RMN. Cette molécule a été testée chez l’animal et a révélé des propriétés anti-obésité. L’ensemble de ce travail a permis d‘identifier plusieurs agonistes puissants du TGR5, lesquels pourraient servir de base à un développement pharmaceutique dans le futur
Bile acids were shown to have antiobesity properties by increasing energy expenditure via activation of a membrane bile acid receptor, TGR5. In this thesis studies, potent TGR5 agonist was widely explored for pharmacological applications of the treatment of metabolic diseases. In the first study, the structure-activity relationship study was performed using 80 natural bile acids, bile acid derivatives. Not only structural feature of bile acid on TGR5 activation, but also several TGR5 agonists were identified as potent TGR5 selective agonists in this study. In the second study, the author paid an attention to a phytosterol, gugulsterone (GS) known as a metabolic modulator. Its effect was reported to be mediated by another bile acid receptor FXR but the author found that GS was a potent TGR5 ligand. Biological activity of GS on Dio2 activation and enhancement of oxygen consumption was observed in animal model and in cell model. This study showed diversity of drug development targeted to the two bille acid receptor, TGR5 and FXR. In the third study, the author attempted screening of TGR5 agonists using 29 plant extracts as a source of compound library. This assay revealed that 21 out of 29 crude extracts were positive. The author succeeded to purify and identify an active compound from one of the positive extract by means of flash chromatography and subsequently NMR analysis. The active compound showed antiobesity effects in an animal. Thus the author could identify the several compounds as potent TGR5 agonists, which could find the pharmacological applications in the future
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Strehle, Axelle. "Characterisation of triterpenoids as TGR5 agonists and their effects on metabolism." Strasbourg, 2009. http://www.theses.fr/2009STRA6149.

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Les dysfonctionnements mitochondriaux sont impliqués dans le développement du diabète mais ne sont pas ciblés par les thérapies disponibles. Les mitochondries sont activées par un RCPG activé par les acides biliaires, le TGR5, une cible intéressante à deux niveaux : pour prévenir les maladies métaboliques (mitochondries) et pour traiter ces maladies (sécrétion de GLP-1). Pour étudier TGR5, il fallait identifier des agonistes sélectifs pour contourner les effets pléiotropiques des acides biliaires, les seuls agonistes connus. Après criblage d’une collection de plantes sur un test d’activité TGR5, les feuilles d’olivier Olea Europaea ont montré une activité TGR5 portée par un triterpène, l’acide oléanolique. In vivo, l’acide oléanolique a une activité anti-hyperglycémique, améliore la tolérance au glucose et empêche la prise de poids. L’acide oléanolique stimule les fonctions mitochondriales dans les muscles in vitro et in vivo. Une étude de SAR sur le squelette des triterpènes nous a permis de synthétiser RG239, un puissant agoniste TGR5 in vitro mais inactif in vivo, probablement à cause d’une faible biodisponibilité. RG239 est un outil pharmacologique intéressant pour étudier la biologie du TGR5. Nous avons ainsi montré que RG239 induit les fonctions mitochondriales de façon TGR5-dépendante. Par ailleurs, RG239 stimule la sécrétion de GLP-1 dans les cellules entéroendocrines intestinales, et cet effet est également TGR5-dépendant. Ces résultats confirment TGR5 comme cible thérapeutique et les triterpènes comme agents thérapeutiques potentiels pour prévenir (mitochondries) et traiter (GLP-1) les maladies métaboliques
Mitochondrial dysfunction is implicated in the early stages of diabetes but is not targeted by the available therapies. Mitochondrial functions can be activated by the bile acids-activated GPCR TGR5, in muscle and in adipose tissue. This double effect of TGR5, on mitochondria and GLP-1 secretion, positions this receptor as an interesting target to prevent the early onset of metabolic diseases. To further explore TGR5 potential, our principal challenge was to identify more potent and more selective TGR5 agonists devoid of the pleiotropic effects of bile acids, the only TGR5 agonists known so far. To this end, we used a TGR5 activity assay to screen a plant library. Among the plant extracts tested, Olea Europaea leaves was shown to exhibit an activity supported by the triterpenoid oleanolic acid. In vivo, oleanolic acid showed anti-hyperglycemic activity, improved glucose tolerance and decreased weight gain. Furthermore, oleanolic acid enhanced mitochondria in muscle both in vitro and in vivo. A SAR study based on the triterpenoid scaffold led us to synthetize RG239, a more potent TGR5 agonist in vitro which is inactive in vivo, probably because of poor bioavailability. RG239 is an interesting pharmacological tool to understand TGR5 biology. Indeed, RG239 was shown to induce mitochondria activity and number in muscle and intestinal cell lines in a TGR5 dependant manner. In addition, RG239 stimulated GLP-1 secretion in intestinal enteroendocrine cells in a TGR5 dependant-manner. Altogether, these results confirm TGR5 as therapeutical target and triterpenoids as potential therapeutical agents in the prevention/mitochondria and treatment/GLP-1 of metabolic diseases
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Baptissart, Marine. "Impacts de concentrations supraphysiologiques d'acides biliaires sur la physiologie testiculaire et les fonctions de reproduction." Thesis, Clermont-Ferrand 2, 2014. http://www.theses.fr/2014CLF22526/document.

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Chez l’homme, des données cliniques décrivent une association entre des pathologies hépatiques et des désordres de la fertilité masculine. Plusieurs modèles expérimentaux de cholestase ont permis de confirmer ce lien et de souligner un impact sur la physiologie testiculaire. De manière intéressante, une telle corrélation existe aussi bien à l’âge adulte que dans des modèles animaux en période pré-pubertaire. Pour autant, le lien moléculaire pouvant expliquer cette association physiopathologique n’a pas été exploré. L’ensemble des hépatopathies a pour dénominateur commun une augmentation des taux plasmatiques d’acides biliaires et ce dès les stades les plus précoces de la maladie. Dans ce contexte, l’hypothèse de l’impact délétère des acides biliaires sur la fonction reproductrice reste à définir. Notre projet de recherche s’articule autour de l’analyse d’un modèle murin d’atteinte hépatique induite par un régime supplémenté en acide cholique. Nos résultats principaux montrent que : 1) lors d’une exposition pubertaire, l’activation supra-physiologique des signalisations Fxrα conduit à un défaut de maturation sexuelle associé à une altération de la fonction endocrine du testicule ; 2) dans un contexte d’exposition à l’âge adulte, l’activation excessive du récepteur membranaire Tgr5 par les acides biliaires est associées à une hypofertilité. Celle-ci s’accompagne d’une altération de la spermatogenèse consécutive à un détachement progressif de l’épithélium séminifère et à une apoptose spécifique des spermatides ; 3) enfin, nos conclusions démontrent pour la première fois l’impact transgénérationnel de l’exposition aux acides biliaires. Sur deux générations successives, les descendants des mâles adultes nourris par un régime supplémenté en acide cholique présentent des anomalies développementales et métaboliques. Dépendantes de l’action de Tgr5, ces dernières sont attribuées à des altérations de l’épigénome des spermatozoïdes issus des mâles exposés aux acides biliaires. En conclusion, nos données démontrent que, dans des conditions cholestatiques, les acides biliaires altèrent les fonctions de reproduction notamment par leurs impacts sur les fonctions testiculaires. Au regard du nombre croissant de personnes souffrant de troubles hépatiques, ces effets délétères des acides biliaires pourraient contribuer à l’augmentation de l’incidence de l’infertilité masculine. Des molécules agonistes des signalisations FXRα et TGR5 sont aujourd’hui envisagées dans le cadre du traitement de pathologies courantes de notre société. Dans ce contexte, notre étude permettra d’alerter les instances sanitaires quant aux conséquences de l’accès à de tels traitements sur la fertilité et la santé des générations futures
Clinical data describe an association between liver diseases and disorders of male fertility. Several experimental models of cholestasis have confirmed this link and highlight an impact on testicular physiology. Interestingly, such correlation exists in adult as well as in during pre-pubertal animals. However, the molecular links have not been explored yet. The increase of plasma bile acids levels is a common feature of liver diseases. In this context, the hypothesis of the deleterious impact of bile acids on reproductive function remains to be defined. For that purpose, we used a mouse model of liver injury induced by a diet supplemented with cholic acid. Main results show that: 1) supra-physiological activation of Fxra, during pubertal period, alters endocrine function of the testis and then sexual maturation. 2) during adult age excessive activation of membrane receptor TGR5 by bile acids leads to subfertility. This is associated with impaired spermatogenesis due to a detachment of the seminiferous epithelium and specific apoptosis of spermatids. 3) Finally, we show for the first time the transgenerational impact of bile acid exposure. Two generations of progenies from males exposed to bile acid-diet show developmental and metabolic abnormalities. These effects, mediated by TGR5, are correlated with alterations of the spermatozoa epigenome. In conclusion, our data demonstrate that bile acids affect reproductive functions with impacts on testicular functions. In line with the increasing number of people with liver diseases, the deleterious effects of bile acids may contribute to the incidence of male infertility. Interestingly, agonists of FXRα and TGR5 are now considered in the treatment of several diseases. In this context, our study might alert health authorities regarding the potential consequences of these treatments on fertility and health futures generations
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4

Pean, Noémie. "Récepteur TGR5 des acides biliaires : impact sur la régénération du foie et l'homéostasie biliaire." Paris 7, 2014. http://www.theses.fr/2014PA077055.

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La composition en AB était plus hydrophobe chez les souris TGR5-K0 par rapport aux souris WT Après HP, une importante nécrose hépatique, une cholestase prolongée, une réponse inflammatoire excessive et un retard de régénération hépatique ont été observés chez les souriE TGR5-KO. La réponse adaptative rénale et biliaire à la surcharge en AB après HP ont fortement été détériorées chez les souris TGR5-K0 par rapport aux souris WT. Le traitement par la cholestyramine et la déplétion en Kupffer, ont significativement amélioré le phénotype des souris TGR5-K0 après HP. Après une ligature de la voie biliaire principale ou un régime enrichi en CA, les TGR5-K0 avaient des lésions hépatiques plus importantes que les souris WT, ainsi qu'une altération de l'élimination urinaire des AB. Chez les souris TGR5-KO, la synthèse hépatocytaire des AB et le shunt cholécystohépatique n'étaient pas altérés, en revanche, un déficit de relaxation vésiculaire et une hyperperméabilité paracellulaire de l'épithélium biliaire étaient observés par rapport aux WT. Le récepteur TGR5 est crucial pour protéger le foie contre la surcharge en AB après HP, principalement par le contrôle de l'hydrophobicité du pool d'AB et de la sécrétion de cytokines. En absence du récepteur TGR5, la stagnation de bile anormalement hydrophobe et l'excès d'inflammation, associés à l'altération du flux biliaire et de l'élimination urinaire des AB, mènent à une surcharge en AB, à l'origine des lésions hépatiques et du retard de régénération. Le récepteur TGR5 contrôlerait l'hydrophobicité du pool d'AB via le contrôle de la fonction motrice de la vésicule biliaire et régulerait la perméabilité de l'épithélium biliaire
BA composition (plasma, liver, bile, urine, stools) was more hydrophobic in TGR5-KO than in W1 mice. After PH, severe hepatocyte necrosis, prolonged cholestasis, exacerbated inflammatory response and delayed regeneration were observed in TGR5-KO mice. Hepatocyte adaptive response to post-PH BA overload was similar in WT and TGR5-KO mice. However, kidney and biliary adaptive responses to post-PH BA overload were strongly impaired in TGR5-KO as compared with WT mice. Cholestyramine treatment, as well as Kupffer cell depletion, significantly improved the post-PH TGR5 KO mice phenotype. After bile duct ligation or upon a cholic acid-enriched diet, TGR5 KO mice exhibited more severe liver injury than WT as well as impaired BA elimination in urine. In TGR5-KO mice, hepatic bile acid synthesis and cholecystohepatic shunt were not altered, but gallbladder relaxation and biliary epithelium hyperpermeability were observed as compared to WT mice. TGR5 is crucial for liver protection against BA overload after PH, primarily through the control of bile hydrophobicity and cytokine secretion. In the absence of TGR5, intrahepatic stasis of abnormally hydrophobic bile and excessive inflammation, in association with impaired bile flow adaptation and deficient urinary BA efflux, lead to BA overload-induced liver injury and delayed regeneration. TGR5 may control both bile acid pool hydrophobicity via the control of gallbladder motor function, and epithelial permeability in the biliary tract
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Prasanna, Kumar Divya. "Regulation of Pancreatic α and β Cell Function by the Bile Acid Receptor TGR5." VCU Scholars Compass, 2014. http://scholarscompass.vcu.edu/etd/3591.

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The discovery that bile acids act as endogenous ligands of the membrane receptor TGR5 and the nuclear receptor FXR increased their significance as regulators of cholesterol, glucose and energy metabolism. Activation of TGR5, expressed on enteroendocrine L cells, by bile acids caused secretion of GLP-1, which stimulates insulin secretion from pancreatic β cells. Expression of TGR5 on pancreatic islet cells and the direct effect of bile acids on the endocrine functions of pancreas, however, are not fully understood. The aim of this study was to identify expression of TGR5 in pancreatic islet cells and determine the effect of bile acids on insulin secretion. Expression of TGR5 was identified by quantitative PCR and western blot in islets from human and mouse, and in α (αTC1-6) and β (MIN6) cells. Release of insulin, glucagon and GLP-1 were measured by ELISA. The signaling pathways coupled to TGR5 activation were identified by direct measurements such as stimulation of G proteins, adenylyl cyclase activity, PI hydrolysis and intracellular Ca2+ in response to bile acids; and confirmed by the use of selective inhibitors that block specific steps in the signaling pathway. Our studies identified expression of TGR5 receptors in β cells and demonstrated that activation of these receptors by both pharmacological ligands (oleanolic acid (OA) and INT-777) and physiological ligand (lithocholic acid, LCA) induced insulin secretion. TGR5 receptors are also expressed in α cells and, activation of TGR5 by OA, INT-777 and LCA at 5 mM glucose induced release of glucagon, which is processed from proglucagon by the selective expression of prohormone convertase 2 (PC2). However, under hyperglycemia, activation of TGR5 in α cells augmented the glucose-induced increase in GLP-1 secretion, which in turn, stimulated insulin secretion. Secretion of GLP-1 from α cells reflected TGR5-mediated increase in PC1 promoter activity and PC1 expression, which selectively converts proglucagon to GLP-1. The signaling pathway activated by TGR5 to mediate insulin and GLP-1 secretion involved Gs/cAMP/Epac/PLC-ε/Ca2+. These results provide insights into the mechanisms involved in the regulation of pancreatic α and β cell function by bile acids and may lead to new therapeutic avenues for the treatment of diabetes.
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Spatz, Madeleine. "Étude du lien entre maladie alcoolique du foie, microbiote intestinal et acides biliaires : rôles spécifiques de la pectine et du récepteur aux acides biliaires TGR5." Thesis, Université Paris-Saclay (ComUE), 2018. http://www.theses.fr/2018SACLS365.

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La maladie alcoolique du foie (MAF) regroupe l’ensemble des lésions qui apparaissent suite à une consommation excessive et chronique d’alcool. A consommation d’alcool égale, les patients n’évolueront pas tous vers les formes sévères de la maladie. Le microbiote intestinal est un cofacteur déterminant dans la sévérité de la MAF. Parmi les métabolites fécaux entre des souris recevant le microbiote intestinal de patients avec des lésions sévères ou non, les acides biliaires ont été identifiés comme les plus discriminants. Le récepteur aux acides biliaires TGR5, exprimé sur les cellules de Kupffer, favorise leur profil anti-inflammatoire.Nous avons évalué l’impact du récepteur TGR5 dans la MAF chez des souris déficientes pour ce récepteur. La déficience en TGR5 aggrave la MAF, sans passer par une modulation de la cellule de Kupffer. C’est en fait le microbiote intestinal qui est impacté chez les souris déficientes pour TGR5, et qui médie cette aggravation.Par ailleurs, afin de moduler le microbiote intestinal au cours de la MAF, nous avons évalué le rôle de la pectine, qui favorise la croissance de certaines bactéries et peut chélater les acides biliaires. Malgré ses propriétés chélatantes, ce sont bien les modifications du microbiote intestinal induites par la pectine qui jouent un rôle protecteur et curatif dans la MAF.Ces différentes études devraient permettre d’identifier des cibles thérapeutiques potentiellement applicables chez des patients alcooliques et basées sur la modulation du microbiote intestinal
Alcoholic liver disease (ALD) includes all the liver injuries occurring as a result of excessive and chronic alcohol consumption. Nevertheless, among heavy drinker, only a subset of individuals will develop severe liver injury. Intestinal microbiota was identified as a major player in the mechanisms involved in ALD. Moreover, bile acids were the most discriminant faecal metabolites between mice with or without liver injury. The bile acids receptor TGR5, which is expressed on Kupffer cells, promotes their anti-inflammatory profile.We assessed the role of bile acids receptor TGR5 in ALD using TGR5-deficient mice. TGR5-deficiency worsens ALD, but without modulating the Kupffer cells profile. However, intestinal microbiota is impaired in TGR5-deficient mice, and this is responsible for ALD worsening.Furthermore, in order to modulate the intestinal microbiota during ALD, we assessed the role of pectin, which is known to promote the growth of certain bacteria and that is a bile acids sequestrant. Despite its sequestrant properties, pectin-induced changes in intestinal microbiota play a protective and curative role in ALD.These studies will allow the identification of new therapeutic targets that could be used for alcoholic patients, using intestinal microbiota modulation
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Moullan, Norman. "Identification and validation of a potent synthetic TGR5 agonist that improves metabolism, inflammation and atherosclerosis." Thesis, Paris, EPHE, 2015. http://www.theses.fr/2015EPHE3070.

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L’obésité, le diabète de type 2 et l’athérosclérose sont les principaux problèmes de santé publique affectant les pays développés. Bien que de nombreux traitements soient disponibles contre ces maladies, de nombreux progrès sont encore nécessaire pour le développement de composés plus actif et plus sûr. Mon laboratoire a montré que l’activation du récepteur aux acides biliaires TGR5 par ses ligands entrainait une augmentation de la dépense énergétique et réduisait le niveau des cytokines chez la souris, ce qui pourrait être une nouvelle voie vers le traitement de ces désordres métaboliques. Nous décrivons ici le développement d’un nouvel agoniste synthétique, spécifique et puissant pour TGR5. A partir d’une librairie de 20.000 composés, les composés 50980906, 13008574 et 37525283 ont été caractérisés comme les plus puissants et stables. Le composé 13008574 a montré une réduction significative sur la prise de poids de souris C57BL/6J après un régime alimentaire riche en graisses. Suite à l’activation de TGR5, nous avons observés une augmentation du niveau d'expression des gènes Ucp-1, Dio-2 et Cpt-1 dans le tissu adipeux brun et une augmentation de la clairance du glucose suite à une augmentation de la sécrétion de GLP-1 chez les souris traitées par le composé 13008574. Nous avons également montrés que le composé 13008574 n’a pas d’effet sur les souris TGR5-/- témoignant de sa spécificité. Enfin nous avons par ailleurs confirmé l'effet du composé 13008574 comme agent anti-inflammatoire, avec un effet protecteur face au développement de l'athérosclérose. Notre travail montre ainsi que le développement d’agonistes pour TGR5, puissant et sûr, est possible pour traiter le syndrome métabolique
Obesity, type 2 diabetes and atherosclerosis, are amongst the main driving factors of a public health crisis that impacts developed countries. Although several drugs are available, there is still a large unmet medical need to find better and safer compounds to treat these diseases. In this context, my host laboratory discovered that activation of the membrane bile acid receptor TGR5 induces energy expenditure and reduces inflammation in mice, which would be beneficial to manage the above–mentioned disorders. INT-777, a semi-synthetic bile acid, is until now, one of the most specific TGR5 ligands. Here, we report the identification of a new synthetic, selective and potent TGR5 agonist. From a screen of 20,000 compounds as potential TGR5 activators, the compounds 50980906, 13008574 and 37525283 were the most potent and stable. In particular, 13008574 induced a significant reduction of body weight gain when C57BL/6J mice were exposed to a high fat diet, paralleled by an increase in the expression levels of Ucp-1, Dio-2 and Cpt-1 in brown adipose tissue. In addition, mice treated with 13008574 displayed improved glucose clearance, consequent to increased GLP-1 secretion. We showed furthermore that the effects of 13008574 were lost in TGR5-/- mice, testifying the specificity of the compound. In addition, 13008574 acts as an anti-inflammatory agent, with a protective effect on atherosclerosis development in LDLr-/- mice treated with a high cholesterol diet. Our work hence shows that potent, selective, and safe TGR5 agonists can be developed to cure the metabolic syndrome
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8

Genet, Cédric. "Identification et développement de triterpènes comme agonistes TGR5 : étude de leurs effets sur le métabolisme." Strasbourg, 2010. http://www.theses.fr/2010STRA6295.

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Les maladies métaboliques sont devenues un fléau ces dernières décennies préfigurant plusieurs maladies graves comme le diabète de type 2. Les disfonctionnements mitochondriaux sont caractéristiques des maladies métaboliques. Cependant, ils ne sont pas ciblés par les thérapies actuelles qui se concentrent plutôt sur les conséquences de ces maladies. Néanmoins, la capacité du récepteur couplé aux protéines G, TGR5 présent dans le tissu adipeux et musculaire à augmenter l’activité mitochondriale ouvre de nouvelles perspectives d’avenir pour prévenir les stades précoce des maladies métaboliques et pour traiter ces maladies. Pour explorer le potentiel de TGR5, notre principal défi était d’identifier des agonistes plus puissants et plus sélectifs que les acides biliaires. En effet, les acides biliaires seuls agonistes connus à ce jour sont aussi actifs sur d’autres récepteurs nucléaires. Dans ce but, nous avons criblé une collection de plantes antidiabétiques par bio-guidage sur TGR5, ce qui nous a permis d’isoler et d’identifier deux principes actifs de la famille des triterpènes, l’acide oléanolique et l’acide corosolique. In vivo, l’acide oléanolique possède une activité hypoglycémiante, améliore la tolérance au glucose et empêche la prise de poids. De plus, l’acide oléanolique augmente l’activité mitochondriale in vitro. Une étude de la relation structure à activité sur une collection plus large de triterpènes naturels nous a permis d’obtenir un chef de file, l’acide bétulinique dont l’hemi-synthèse d’analogues a fourni RG 239, un puissant agoniste TGR5 capable d’induire l’activité mitochondriale de façon TGR5-dépendante. Malgré cela, in vivo il n’a montré aucun effet probablement à cause d’une faible biodisponibilité. Bien que tous ces résultats confirment TGR5 comme une cible thérapeutique, nous nous sommes rendus à l’évidence que les triterpènes ne sont pas des molécules développables pour obtenir un médicament. En effet, leurs châssis hydrophobe et le faible degré de liberté qu’offre leurs fonctions chimiques pour des modifications structurales nous ont poussés à utiliser des outils chémoinformatiques pour découvrir une nouvelle famille d’agoniste TGR5. C’est pourquoi, le criblage des banques de données de produits commerciaux Zinc et Asinex a été réalisé par des recherches pharmacophoriques et topomériques dont les résultats sont en cours d’exploitation
Mitochondrial dysfunction, a hallmark feature in the early stage of metabolic diseases, is currently not targeted by the available therapies with preferentially focus on the consequence of the diseases. Nevertheless, an early discovered G coupled protein receptor named TGR5 was shown to lead to an increase in mitochondrial activity. This effect reveals TGR5 as an interesting target to prevent the early onset of metabolic diseases. To further explore TGR5 potential, our principal challenge was to identify more potent and more selective TGR5 agonists than the already known bile acids which act on other nuclear receptors. To this end we used a TGR5 activity assay to screen a plant library. Among the plant extracts tested, was have been able to isolated two active principles from the triterpene family, the oleanolic acid and the corosolic acid. In vivo, oleanolic acid showed antihyperglycemic activity, improved glucose tolerance and decrease weight gain. Furthermore, oleanolic acid enhanced mitochondrial activity in vitro. An SAR study based on natural triterpenes has led us to the discovery of betulinic acid used in hemi-synthesis and affords the synthesis of RG 239, a more potent TGR5 agonist which induce mitochondrial activity in a TGR5 dependant manner. Unfortunately, RG 239 was not active in vivo, probably because of poor bioavailability. Although, these results confirm TGR5 as therapeutical target, we have found that triterpenes were not drugable molecules. Indeed, triterpenes are hydrophobic molecules and the degree of liberty of their chemical function for structural modification is very low. That is the reason why we have decided to screen two databases of commercial products, Zinc and Asinex with a scaffold hoping method in order to find new TGR5 agonist family. The selected molecules by this approach are under investigation
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9

Deutschmann, Kathleen [Verfasser], and Verena [Akademischer Betreuer] Keitel-Anselmino. "Die Rolle des Gallensalzrezeptors TGR5 (GPBAR1) in gastrointestinalen Tumoren / Kathleen Deutschmann ; Betreuer: Verena Keitel-Anselmino." Düsseldorf : Universitäts- und Landesbibliothek der Heinrich-Heine-Universität Düsseldorf, 2021. http://d-nb.info/1236399595/34.

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Spengler, Joseph R. "Diabetes-Induced Expression and Regulation of GLP-1 levels by Bile Acid Receptors (TGR5 & FXR)." VCU Scholars Compass, 2017. http://scholarscompass.vcu.edu/etd/4776.

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Diabetes Mellitus has continued to drastically affect the health of the world and many complications can prove fatal. As long as this metabolic disease persist, research discoveries will need to continue to be made so that patient outcomes and healthcare are dramatically enhanced. In recent years, GLP-1 has been the topic of conversation for diabetes research, due to its promising effects in promoting insulin sensitivity. Furthermore, bile acids and their receptors (TGR5 & FXR) have shown promise in their actions in the regulation of GLP-1, and thus glucose homeostasis. Here we have shown the detection and increased expression of TGR5 and GLP-1, and decreased expression of FXR in diabetic mouse intestinal mucosa tissues. We have also shown the detection and increased expression of these receptors in STC-1 cells. More importantly we have linked the connection of increased glucose concentration (hyperglycemia) to increased TGR5 activation to increased GLP-1 release, thus leading to increased insulin sensitivity and altered diabetic outcomes.
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Books on the topic "TGR5"

1

Rajagopal, Senthilkumar, and Murugavel Ponnusamy. Metabotropic GPCRs: TGR5 and P2Y Receptors in Health and Diseases. Singapore: Springer Singapore, 2018. http://dx.doi.org/10.1007/978-981-13-1571-8.

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TFQ, ed. From The Four Quarters Magazine: excerpt from TGR. India: The Four Quarters Magazine, 2013.

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United States. Environmental Protection Agency, ed. LandView III, Environmental Mapping Software, CD-TGR95-LV3-11, December 1997, (CD-ROM). [S.l: s.n., 1998.

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United States. Environmental Protection Agency, ed. LandView 3, Environmental Mapping Software, CD-TGR95-LV3-7, Disc 7 of 10, LA, TX, December 1997, (CD-ROM). [S.l: s.n., 1998.

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Negara, Indonesia Sekretariat, ed. Apresiasi pengawasan dan tuntutan perbendaharaan/tuntutan ganti rugi (TP/TGR) dalam mendukung akuntabilitas kinerja Sekretariat Negara: Proceeding. [Jakarta]: Sekretariat Negara RI, 2003.

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United States. Environmental Protection Agency, ed. LandView 3, Environmental Mapping Software, CD-TGR95-LV3-3, Disc 3 of 10, AL, FL, GA, MS, December 1997, (CD-ROM). [S.l: s.n., 1998.

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United States. Environmental Protection Agency, ed. LandView 3, Environmental Mapping Software, CD-TGR95-LV3-6, Disc 6 of 10, AR, KS, MO, OK, December 1997, (CD-ROM). [S.l: s.n., 1998.

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United States. Environmental Protection Agency, ed. LandView 3, Environmental Mapping Software, CD-TGR95-LV3-2, Disc 2 of 10, NC, SC, TN, VA, WV, December 1997, (CD-ROM). [S.l: s.n., 1998.

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United States. Environmental Protection Agency, ed. LandView 3, Environmental Mapping Software, CD-TGR95-LV3-4, Disc 4 of 10, IL, IN, KY, MI, OH, December 1997, (CD-ROM). [S.l: s.n., 1998.

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United States. Environmental Protection Agency, ed. LandView 3, Environmental Mapping Software, CD-TGR95-LV3-8, Disc 8 of 10, AZ, CO, NE, NM, UT, December 1997, (CD-ROM). [S.l: s.n., 1998.

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Book chapters on the topic "TGR5"

1

Rajagopal, Senthilkumar, and Murugavel Ponnusamy. "TGR5 Receptor." In Metabotropic GPCRs: TGR5 and P2Y Receptors in Health and Diseases, 19–37. Singapore: Springer Singapore, 2018. http://dx.doi.org/10.1007/978-981-13-1571-8_2.

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Keitel, Verena, Christoph G. W. Gertzen, Sven Schäfer, Caroline Klindt, Christina Wöhler, Kathleen Deutschmann, Maria Reich, Holger Gohlke, and Dieter Häussinger. "Bile Acids and TGR5 (Gpbar1) Signaling." In Mammalian Sterols, 81–100. Cham: Springer International Publishing, 2020. http://dx.doi.org/10.1007/978-3-030-39684-8_4.

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Rajagopal, Senthilkumar, and Murugavel Ponnusamy. "Therapeutically Targeting TGR5 and P2Y Receptors." In Metabotropic GPCRs: TGR5 and P2Y Receptors in Health and Diseases, 57–76. Singapore: Springer Singapore, 2018. http://dx.doi.org/10.1007/978-981-13-1571-8_4.

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Macchiarulo, Antonio, Antimo Gioiello, and Roberto Pellicciari*. "Chapter 10. TGR5 Agonists in Development." In Drug Discovery, 270–305. Cambridge: Royal Society of Chemistry, 2012. http://dx.doi.org/10.1039/9781849735322-00270.

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Rajagopal, Senthilkumar, and Murugavel Ponnusamy. "Overview of G-Protein Coupled Receptor." In Metabotropic GPCRs: TGR5 and P2Y Receptors in Health and Diseases, 1–18. Singapore: Springer Singapore, 2018. http://dx.doi.org/10.1007/978-981-13-1571-8_1.

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Rajagopal, Senthilkumar, and Murugavel Ponnusamy. "P2Y Receptor." In Metabotropic GPCRs: TGR5 and P2Y Receptors in Health and Diseases, 39–55. Singapore: Springer Singapore, 2018. http://dx.doi.org/10.1007/978-981-13-1571-8_3.

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Keitel, Verena, Jan Stindt, and Dieter Häussinger. "Bile Acid-Activated Receptors: GPBAR1 (TGR5) and Other G Protein-Coupled Receptors." In Bile Acids and Their Receptors, 19–49. Cham: Springer International Publishing, 2019. http://dx.doi.org/10.1007/164_2019_230.

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Thomas, C., J. Auwerx, and K. Schoonjans. "Linking nutrition and metabolism, a role for the membrane bile acid receptor TGR5." In Bile Acid Biology and Therapeutic Actions, 145–50. Dordrecht: Springer Netherlands, 2009. http://dx.doi.org/10.1007/978-1-4020-9644-0_19.

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Keitel, V., K. Cupisti, R. Kubitz, and D. Häussinger. "Expression and localization of the membrane-bound bile acid receptor TGR5 in human gallbladder tissue." In Bile Acid Biology and Therapeutic Actions, 82–85. Dordrecht: Springer Netherlands, 2009. http://dx.doi.org/10.1007/978-1-4020-9644-0_12.

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Chen, Peng, Jinyou Lu, Zhongwu Jin, Yinjun Zhou, Rouxin Tang, Zhaoxi Liu, and Qiuba Han. "Spatiotemporal Evolution Characteristics and Influencing Factors of Incoming Water and Sediment in Three Gorges Reservoir." In Lecture Notes in Civil Engineering, 1535–52. Singapore: Springer Nature Singapore, 2023. http://dx.doi.org/10.1007/978-981-19-6138-0_136.

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AbstractBased on the hydrological and sediment observation data of the main stream and main stream of the upper Yangtze River from 1956 to 2018, using M-K test, Wavelet analysis, Approximate entropy and Lyapunov exponent, this paper analyzes the spatiotemporal evolution characteristics from the perspectives of catastrophe, periodicity, complexity and chaos of incoming water and sediment in The TGR (TGR), defines the connotation of “new water and sediment conditions” in the TGR, and discusses the main influencing factors of spatiotemporal variation of incoming water and sediment in the TGR. The results show that: (1) Except Pingshan station of Jinsha River, Fushun station of Tuojiang River and Wulong station of Wujiang River, the runoff of other main and tributaries and TGR in the upper Yangtze River has no significant change, but the sediment discharge has obvious mutation, and the runoff and sediment have periodic changes in different degrees; (2) The complexity of annual runoff and sediment transport in the TGR increases gradually, and the complexity of sediment transport is greater than that of runoff. Both annual runoff and sediment transport are chaotic, and the complexity of runoff and sediment transport sequence increases gradually from the upper reaches to the lower reaches; (3) The connotation of “new water and sediment condition” shows that there is no obvious mutation in runoff and sediment transport in time scale, the main cycle of water and sediment change is basically the same, and the complexity and chaos of sediment transport in space scale are significantly greater than runoff, and the change degree of sediment transport is more significant than runoff; (4) From 1991 to 2002, climate change (rainfall) was an important factor affecting the sediment discharge in the upper Yangtze River. From 2003 to 2018, the impact of climate change was relatively insignificant, and human activities became the most important factor.
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Conference papers on the topic "TGR5"

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Ahmed, Sumaya, and Nasser Rizk. "The Expression of Bile Acid Receptor TGR5 in Adipose Tissue in Diet-Induced Obese Mice." In Qatar University Annual Research Forum & Exhibition. Qatar University Press, 2020. http://dx.doi.org/10.29117/quarfe.2020.0212.

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Bile acids are significant physiological factors for digestion, solubilization, absorption, toxic metabolites and xenobiotics. In addition, bile acids are responsible of signal transduction as well as metabolic regulation that activate several receptors such as farnesoid X receptor (FXR) and the membrane G-protein receptor 5 (TGR5). Activation of TGR5 by bile acids is associated with prevention of obesity as well as ameliorating the resistance to insulin via increasing energy expenditure. The objective of this research is to investigate TGR5 gene expression level in different fat depots including visceral or epididymal adipose tissue (eWAT), brown adipose tissue and inguinal adipose tissue (iWAT) and to study the response of TGR5 gene expression to the antiobesity treatment (SFN). Three groups of male CD1 mice were used in this study; lean group fed with SCD, DIO mice on HFD and DIO obese mice treated with anti-obesity treatment. Body weight (BW) and phenotype data were evaluated by weekly including blood samples for analysis of glucose, insulin, leptin, triglycerides (TG). Total RNA was extracted from different fat depots and RT-PCR profiler array technology was used to in order to assess the mRNA expression of TGR5 and leptin. There was significant downregulation of TGR5 gene expression level in obese (DIO) mice and remarkable upregulation of TGR5 gene expression after successful weight loss in DIO mice treated with SFN in time dependent manner at 1 weeks and 4 weeks of ip applications. In conclusion, obesity is associated with decrease in expression of TGR5 in different fat depots and treatment with anti-obesity drug (Sulforaphane) causes stepwise upregulation of TGR5 gene expression in epididymal white adipose tissue parallel stepwise decrease in body weight. Increase of expression of TGR5 in DIO mice in eWAT is accompanied by improvement in glucose homeostasis and insulin action.
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XAVIER, WILLIAM, FRANCISCO ERNANI ALVES MAGALHãES, ANTONIO EUFRáSIO VIEIRA NETO, ANTONIO ROMáRIO COELHO ALCâNTARA, KALINA KELMA OLIVEIRA DE SOUSA, MICHELINE SOARES COSTA OLIVEIRA, and ANA CRISTINA DE OLIVEIRA MONTEIRO MOREIRA. "ESTUDO IN SILICO DAS BASES MOLECULARES DE INTERAÇÃO ENTRE O ÁCIDO OLEANÓLICO E O RECEPTOR TGR5." In II Brazilian Congress of Development. DEV2021, 2021. http://dx.doi.org/10.51162/brc.dev2021-0056.

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Os estudos sobre metabolismo vêm sendo potencializados com as investigações sobre produtos naturais e suas atividades biotecnológicas. Com base nisto, o trabalho investiga a interação molecular do ácido oleanólico com o receptor TGR5 (receptor 1 de ácido biliar acoplado à proteína G), também conhecido como receptor 19 acoplado à proteína G, relatado em diversos modelos experimentais como integrante das moléculas responsáveis por regulações metabólicas capazes de exercer efeitos benéficos contra o diabetes e síndrome metabólica. O ácido oleanólico é um componente natural de muitos alimentos vegetais e ervas medicinais, já o TGR5 é um receptor proteico endógeno ligado à membrana plasmática, expresso em todo o corpo, mas apresenta níveis elevados de expressão no fígado, intestino, estômago, baço, e tecido adiposo marrom. Para promover esta interação in silico, foram obtidas as estruturas tridimensionais das duas moléculas em bancos de dados estruturais e foi realizado o docking molecular, que consiste numa complexação guiada por algoritmo e software especializado, para obtenção de complexos estruturais estáveis. Os resultados descrevem que o ácido oleanólico possui afinidade por um sítio específico do receptor TGR5, se complexando a partir de 6 ligações químicas e as atividades biotecnológicas promovidas por ele possuem alta reprodutibilidade e afinidade, o que é capaz de promover estabilização energética do receptor envolvido, no contexto metabólico, atuando como um aliado no combate à obesidade.,
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Deutschmann, K., M. Reich, A. Lang, R. Piekorz, C. Gertzen, H. Gohlke, D. Häussinger, and V. Keitel. "Role of the bile acid receptor TGR5 (GPBAR1) in cholangiocarcinoma (CCA)." In 35. Jahrestagung der Deutschen Arbeitsgemeinschaft zum Studium der Leber. Georg Thieme Verlag KG, 2019. http://dx.doi.org/10.1055/s-0038-1677201.

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Naisar, S., C. Klindt, M. Reich, T. Luedde, and V. Keitel. "Targeted deletion of Tgr5 in the intestine leads to less biliary damage in cholestasis." In 37. Jahrestagung der Deutschen Arbeitsgemeinschaft zum Studium der Leber. Georg Thieme Verlag KG, 2021. http://dx.doi.org/10.1055/s-0040-1721958.

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Klindt, C., M. Reich, B. Hellweg, J. Stindt, J. Rahnenführer, J. Hengstler, K. Köhrer, K. Schoonjans, D. Häussinger, and V. Keitel-Anselmino. "The G protein coupled bile acid receptor TGR5 (Gpbar1) modulates endothelin-1 signaling in liver." In 36. Jahrestagung der Deutschen Arbeitsgemeinschaft zum Studium der Leber. Georg Thieme Verlag KG, 2020. http://dx.doi.org/10.1055/s-0039-3402102.

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Deutschmann, K., M. Reich, A. Lang, R. Piekorz, C. Gertzen, H. Gohlke, D. Häussinger, T. Luedde, and V. Keitel. "Role of the bile acid receptor TGR5 (GPBAR1) in cholangiocarcinoma (CCA) progression and tumor spread." In 37. Jahrestagung der Deutschen Arbeitsgemeinschaft zum Studium der Leber. Georg Thieme Verlag KG, 2021. http://dx.doi.org/10.1055/s-0040-1722044.

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Reich, M., J. Stindt, K. Deutschmann, P. Lang, D. Häussinger, and V. Keitel. "Upregulation of TGR5 (Gpbar1) in macrophages protects mice from lipopolysaccharide and Listeria monocytogenes-induced liver damage." In 35. Jahrestagung der Deutschen Arbeitsgemeinschaft zum Studium der Leber. Georg Thieme Verlag KG, 2019. http://dx.doi.org/10.1055/s-0038-1677097.

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Reich, M., L. Spomer, J. Höhne, J. Stindt, JR Hov, TH Karlsen, C. Schramm, et al. "TGR5 (Gpbar-1) expression is downregulated in biliary epithelial cells in livers of PSC patients and in Abcb4-/- mice." In 37. Jahrestagung der Deutschen Arbeitsgemeinschaft zum Studium der Leber. Georg Thieme Verlag KG, 2021. http://dx.doi.org/10.1055/s-0040-1721944.

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Gandossi, L., K. Simola, and Adam Toft. "Risk Informed In-Service-Inspection Activities of the ENIQ Task Group on Risk." In ASME 2009 Pressure Vessels and Piping Conference. ASMEDC, 2009. http://dx.doi.org/10.1115/pvp2009-77241.

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The European Network for Inspection Qualification (ENIQ) was established in 1992 in response to increasing recognition of the importance of qualification of non-destructive inspection systems used in in-service inspection programmes for nuclear power plants. Driven by European Nuclear utilities and managed by the European Commission Joint Research Centre (JRC), ENIQ represents a network in which the available resources and expertise can be pooled at European level. ENIQ has recognized the importance of addressing, at European level, the issue of optimizing inspection strategies on the basis of risk by establishing a Task Group on Risk (TGR). Membership of TGR is drawn from European nuclear utilities and consultants. ENIQ TGR is focused on Risk-Informed In-Service Inspection (RI-ISI) methodologies. Its work is directed towards harmonisation in the field of codes, standards and best practice for RI-ISI methodologies, with the objective of increasing the safety of European nuclear power plants. In March 2005 TGR published a European Framework Document for RI-ISI. This publication provides guidance for both developing new RI-ISI approaches and using or adapting established approaches to a European environment, taking into account utility-specific characteristics and national regulatory requirements. More recently, ENIQ TGR has been working at producing more detailed recommended practices and discussion documents on several RI-ISI related issues, such as the role of ISI within the philosophy of defence-in-depth, the verification and validation of structural reliability models (SRMs) to be used in RI-ISI programmes, the use of expert panels and the applicability of RI-ISI to the reactor pressure vessel. Work is ongoing to develop a discussion document on updating of RI-ISI programmes, and new initiatives were launched to study topics such as what magnitude of risk reduction is reasonable to achieve through ISI, and how to set inspection targets, following the selection of ISI sites. In addition, TGR has been active in initiating international projects linked closely to its work, such as the JRC-OECD/NEA co-ordinated RI-ISI benchmark exercise (RISMET), and the project on the relation between inspection qualification and RI-ISI. This paper describes the key activities and publications of TGR to date.
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Zhang, HaoBo, JianHui Wang, and GuoChen Sang. "Experimental research on TGRM cementitious grouting materials performance." In 2011 International Conference on Electronics, Communications and Control (ICECC). IEEE, 2011. http://dx.doi.org/10.1109/icecc.2011.6067975.

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Reports on the topic "TGR5"

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Yingling, Jonathan, and Kiao-Fan Wang. Breast Tumorigenesis: Interaction of Two Signaling Pathways -- TGR-Beta Versus Estrogen Receptor. Fort Belvoir, VA: Defense Technical Information Center, September 1995. http://dx.doi.org/10.21236/ada302267.

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Guo, Shangqin, and Gail Sonenshein. Role of TGR-B1-Mediated Down Regulation of NF-kB/Rel Activity During Growth Arrest of Breast Cancer Cells. Fort Belvoir, VA: Defense Technical Information Center, May 2001. http://dx.doi.org/10.21236/ada396154.

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