Novel Small Molecule Agonist of TGR5 Possesses Anti-Diabetic Effects but Causes Gallbladder Filling in Mice

Briere, Daniel A.; Ruan, Xiaoping; Cheng, Christine; Siesky, Angela M.; Fitch, Thomas; Domı́nguez, Carmen; Sanfeliciano, Sonia Gutiérrez; Montero, Carlos Closa; Suen, Chen S.; Xu, Yanping; Coşkun, Tamer; Michael, M. Dodson

doi:10.1371/journal.pone.0136873

Cited by 65 publications

(84 citation statements)

References 30 publications

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“…In contrast, the administration of different TGR5 agonists (66α-ethyl-23(S)-methylcholic acid (INT-777), compound 18 or compound 23 g) triggered gallbladder filling and an increase in gallbladder size to up to 230% in wildtype mice (with compound 23 g) [5,21,23] . Although gallbladder hypomotility as observed in TGR5 knockout mice represents a known risk factor for cholesterol gallstone development [21,27] , TGR5 knockout mice were protected from cholesterol gallstone formation when fed a lithogenic diet [4] .…”

Section: Tgr5 In Liver Damage: Insights From Tgr5 Knockout Micementioning

confidence: 99%

“…Therefore, TGR5 has emerged as an attractive drug target for metabolic diseases and various TGR5 agonists have been developed [5,23,24,[36][37][38][39][40] .…”

Section: Tgr5 In Liver Damage: Insights From Mice Treated With Varioumentioning

confidence: 99%

“…Despite the desired increase in GLP-1 secretion and improved glucose tolerance, the administration of systemically available TGR5 ligands leads to relaxation of gallbladder smooth muscle cells and an increased gallbladder filling and volume, which may cause unwanted side effects such as discomfort, pain and gallstone development [5,20,21,23] . Furthermore, due to the extremely high expression of TGR5 in gallbladder tissue as compared to other tissues such as the intestine, effects on gallbladder filling were observed with lower concentrations of a TGR5 agonist (compound 18) as effects on GLP-1 secretion [5] .…”

Section: Tgr5 In Liver Damage: Insights From Mice Treated With Varioumentioning

confidence: 99%

“…Both human and murine gallbladder tissues express by far the highest TGR5 mRNA levels [4][5][6] . Various unconjugated and conjugated BA represent ligands for TGR5, with taurine-conjugated lithocholic acid (EC 50 0.29 μ M ) and taurodeoxycholic acid (TDCA; EC 50 0.79 μ M ) being the most potent endogenous BA agonists [1,2,[7][8][9][10] .…”

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confidence: 99%

“…TGR5 is also expressed in the epithelial cells and the smooth muscle cells of the gallbladder [6,21,22] . While activation of the receptor in the epithelium triggers chloride and fluid secretion, stimulation of TGR5 in the muscle cells results in relaxation and gallbladder filling [5,6,[21][22][23] . TGR5 was not detected in quiescent HSC by immunofluorescence staining [12] , but TGR5 mRNA and protein expression is upregulated when HSC become activated and transform into myofibroblast-like cells (Keitel and Häussinger [11] unpublished data).…”

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confidence: 99%

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Role of the G Protein-Coupled Bile Acid Receptor TGR5 in Liver Damage

Reich

Klindt²,

Deutschmann³

et al. 2017

Dig Dis

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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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Section: Tgr5 In Liver Damage: Insights From Tgr5 Knockout Micementioning

confidence: 99%

“…Therefore, TGR5 has emerged as an attractive drug target for metabolic diseases and various TGR5 agonists have been developed [5,23,24,[36][37][38][39][40] .…”

Section: Tgr5 In Liver Damage: Insights From Mice Treated With Varioumentioning

confidence: 99%

Section: Tgr5 In Liver Damage: Insights From Mice Treated With Varioumentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Role of the G Protein-Coupled Bile Acid Receptor TGR5 in Liver Damage

Reich

Klindt²,

Deutschmann³

et al. 2017

Dig Dis

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TGR5 (GPBAR1) in the Liver

et al. 2020

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Functions of the Gallbladder

Housset

Chrétien

Debray

et al. 2016

Comprehensive Physiology

127

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The gallbladder stores and concentrates bile between meals. Gallbladder motor function is regulated by bile acids via the membrane bile acid receptor, TGR5, and by neurohormonal signals linked to digestion, for example, cholecystokinin and FGF15/19 intestinal hormones, which trigger gallbladder emptying and refilling, respectively. The cycle of gallbladder filling and emptying controls the flow of bile into the intestine and thereby the enterohepatic circulation of bile acids. The gallbladder also largely contributes to the regulation of bile composition by unique absorptive and secretory capacities. The gallbladder epithelium secretes bicarbonate and mucins, which both provide cytoprotection against bile acids. The reversal of fluid transport from absorption to secretion occurs together with bicarbonate secretion after feeding, predominantly in response to an adenosine 3',5'-cyclic monophosphate (cAMP)-dependent pathway triggered by neurohormonal factors, such as vasoactive intestinal peptide. Mucin secretion in the gallbladder is stimulated predominantly by calcium-dependent pathways that are activated by ATP present in bile, and bile acids. The gallbladder epithelium has the capacity to absorb cholesterol and provides a cholecystohepatic shunt pathway for bile acids. Changes in gallbladder motor function not only can contribute to gallstone disease, but also subserve protective functions in multiple pathological settings through the sequestration of bile acids and changes in the bile acid composition. Cholecystectomy increases the enterohepatic recirculation rates of bile acids leading to metabolic effects and an increased risk of nonalcoholic fatty liver disease, cirrhosis, and small-intestine carcinoid, independently of cholelithiasis. Among subjects with gallstones, cholecystectomy remains a priority in those at risk of gallbladder cancer, while others could benefit from gallbladder-preserving strategies. © 2016 American Physiological Society. Compr Physiol 6:1549-1577, 2016.

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Novel Small Molecule Agonist of TGR5 Possesses Anti-Diabetic Effects but Causes Gallbladder Filling in Mice

Cited by 65 publications

References 30 publications

Role of the G Protein-Coupled Bile Acid Receptor TGR5 in Liver Damage

Role of the G Protein-Coupled Bile Acid Receptor TGR5 in Liver Damage

TGR5 (GPBAR1) in the Liver

Functions of the Gallbladder

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