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7-Methylation of Chenodeoxycholic Acid Derivatives Yields a Substantial Increase in TGR5 Receptor Potency.

TGR5 agonists are potential therapeutics for a variety of conditions including type 2 diabetes, obesity, and inflammatory bowel disease. After screening a library of chenodeoxycholic acid (CDCA) derivatives, it was determined that a range of modifications could be made to the acid moiety of CDCA which significantly increased TGR5 agonist potency. Surprisingly, methylation of the 7-hydroxyl of CDCA led to a further dramatic increase in potency, allowing the identification of 5.6 nM TGR5 agonist 17.

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Chenodeoxycholic Acid: An Update on Its Therapeutic Applications.

Chenodeoxycholic acid (CDCA), 3α,7α-dihydroxy-5β-cholan-24-oic acid, is a primary bile acid generated in the liver from cholesterol. In liver cells CDCA is conjugated with glycine or taurine to form two bile salts, Glyco-CDCA and Tauro-CDCA, before being released into the bile ducts. In the intestine, CDCA is further metabolized to generate a 7β epimer, i.e., the ursodeoxycholic acid (UDCA), or dehydroxylate to generate lithocolic acid (LCA). In humans, CDCA is the physiological ligand for the bile acid sensor farnesoid X receptor (FXR), while LCA is a potent agonist for a G protein-coupled receptor, known as GPBAR1 (TGR5). Along with UDCA, CDCA has been clinically used for the dissolution of gallbladder stones at doses ranging from 375 to 750 mg/day, with a success rate of 8 to 18%. Because the efficacy of CDCA was significantly lower than that of UDCA and 18-30% of patients developed significant side effects, the most frequent being diarrhea and a reversible increase in aminotransferases plasma levels, this application has lost its therapeutic relevance. Additionally, the combination of CDCA with UDCA, generally at doses of 5-10 mg/kg each, has failed to provide significant advantages over UDCA alone. In 2017, CDCA has been approved as an orphan indication for the treatment of patients with cerebrotendinous xanthomatosis (CTX), a rare autosomal recessive disorder caused by mutations of sterol 27-hydroxylase (CYP27A1) gene. Since CYP27A1 is essential for cholesterol breakdown, CTX patients develop abnormal lipid storage with increased plasma and tissue levels of cholestanol and very low/absent production of CDCA. CDCA is a potent inhibitor of CYP27A1, and early initiation of CDCA therapy, at doses up to 750 mg/day, is considered the standard medical therapy for CTX resulting in decreased plasma levels of cholestanol and stabilization of neurologic symptoms. Studies in CTX patients have also shown that CDCA might suppress the activity of 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase in the liver. Furthermore, CDCA promotes the release of glucagon-like peptide-1 (GLP-1) in diabetic patients, likely by activating GPBAR1.

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Potential of Intestine-Selective FXR Modulation for Treatment of Metabolic Disease.

Farnesoid X receptor controls bile acid metabolism, both in the liver and intestine. This potent nuclear receptor not only maintains homeostasis of its own ligands, i.e., bile acids, but also regulates glucose and lipid metabolism as well as the immune system. These findings have led to substantial interest for FXR as a therapeutic target and to the recent approval of an FXR agonist for treating primary biliary cholangitis as well as ongoing clinical trials for other liver diseases. Given that FXR biology is complex, including moderate expression in tissues outside of the enterohepatic circulation, temporal expression of isoforms, posttranscriptional modifications, and the existence of several other bile acid-responsive receptors such as TGR5, clinical application of FXR modulators warrants thorough understanding of its actions. Recent findings have demonstrated remarkable physiological effects of targeting FXR specifically in the intestine (iFXR), thereby avoiding systemic release of modulators. These include local effects such as improvement of intestinal barrier function and intestinal cholesterol turnover, as well as systemic effects such as improvements in glucose homeostasis, insulin sensitivity, and nonalcoholic fatty liver disease (NAFLD). Intriguingly, metabolic improvements have been observed with both an iFXR agonist that leads to production of enteric Fgf15 and increased energy expenditure in adipose tissues and antagonists by reducing systemic ceramide levels and hepatic glucose production. Here we review the recent findings on the role of intestinal FXR and its targeting in metabolic disease.

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GPBAR1 Functions as Gatekeeper for Liver NKT Cells and provides Counterregulatory Signals in Mouse Models of Immune-Mediated Hepatitis.

GPBAR1, also known as TGR5, is a G protein-coupled receptor activated by bile acids. Hepatic innate immune cells are involved in the immunopathogenesis of human liver diseases and in several murine hepatitis models. Here, by using genetic and pharmacological approaches, we provide evidence that GPBAR1 ligation attenuates the inflammation in rodent models of hepatitis.

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The protective effects of TGR5 against ultraviolet B irradiation in epidermal stem cells.

Repetitive exposure to ultraviolet radiation (UVR) results in continuous insults to the skin, including continuous loss of the capacities of epidermal stem cells (ESCs). Takeda G-protein-coupled receptor-5 (TGR5) participates in a variety of physiological activities, but its biological function in skin has not been reported. In this study, we report that TGR5 could be detected in ESCs and its expression was reduced after ultraviolet B (UV-B) irradiation. Treatment with the specific TGR5 agonist 3-(2-chlorophenyl)-N-(4-chlorophenyl)-N,5-dimethylisoxazole-4-carboxamide (GPBARA) prevented UV-B-induced oxidative stress by reducing 4-hydroxy-2-nonenal and increasing the level of glutathione. We also found that the presence of GPBARA improved UV-B irradiation-induced mitochondrial dysfunction by elevating mitochondrial membrane potential. Interestingly, our results indicate that GPBARA pretreatment suppressed UV-B irradiation-induced reduced cell viability, release of lactic dehydrogenase, and secretion of high mobility group box 1. Notably, GPBARA pretreatment inhibited UV-B irradiation-induced decrease in integrin β1 and Krt19, dependent on TGR5. Mechanistically, we found that the activation of TGR5 by GPBARA increased Wnt1, Wnt3a, Myc, and cyclin D1 in ESCs. Our data suggest a new function of TGR5 in regulating ESCs.

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The potential use of grape phytochemicals for preventing the development of intestine-related and subsequent inflammatory diseases.

Grape phytochemicals prevent intestine-related and subsequent other inflammatory diseases. Phytochemicals and vitamin D are useful for the regulation of inflammatory responses. Phytochemicals is the generic name of terpenoids, carotenoids and flavonoids that consist of a variety of chemicals contained in vegetables and fruits. There are a variety of grape cultivars that contain many kinds of phytochemicals in their skin and seeds. Grape phytochemicals including grape seed extracts (GSE) have already been used to maintain healthy condition through manipulating inflammatory responses by decreasing the expression of inflammation-related factors.

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Activation of G-protein-coupled bile acid receptor Gpbar1 (TGR5) inhibits degradation of type II collagen and aggrecan in human chondrocytes.

Abnormal loss of components of the extracellular matrix (ECM) including type II collagen and aggrecan caused by proinflammatory cytokines such as tumor necrosis factor-α (TNF-α) is an important pathophysiological characteristic of osteoarthritis (OA). G-protein-coupled bile acid receptor, Gpbar1 (TGR5), is an important member of the bile acid receptor subclass of G Protein-Coupled Receptors (GPCRs). Little information regarding the effects of TGR5 in the pathological development of OA has been reported before. In the current study, we showed that TGR5 is expressed in human primary chondrocytes and human chondrosarcoma SW1353 cells. Interestingly, expression of TGR5 was reduced in response to TNF-α treatment in SW1353 cells. Our results indicate that activation of TGR5 using its specific agonist INT-777 reduced TNF-α-induced degradation of the articular ECM, including type II collagen and aggrecan, by inhibiting expression of matrix metalloproteinase-3 (MMP-3), MMP-13, a disintegrin and metalloproteinase with thrombospondin motifs- 4 (ADAMTS-4) and ADAMTS-5. We also found that INT-777 treatment inhibited phosphorylation of p38 and activation of the IκB kinase/inhibitory κBα/nuclear factor- κB (IKK/IκBα/NF-κB) signaling pathway. Notably, knockdown of TGR5 abolished the protective effects of INT-777 against ECM degradation, suggesting the involvement of TGR5. Our findings implicate that TGR5 might be considered as a potential therapeutic target for the treatment of OA.

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Differential action of TGR5 agonists on GLP-2 secretion and promotion of intestinal adaptation in a piglet short bowel model.

Enteroendocrine L cells and glucagon-like peptide 2 (GLP-2) secretion are activated in the intestinal adaptation process following bowel resection in patients with short bowel syndrome. We hypothesized that enteral activation of Takeda G protein-coupled receptor 5 (TGR5), expressed in enteroendocrine L cells, could augment endogenous GLP-2 secretion and the intestinal adaptation response. Our aim was to assess the efficacy of different TGR5 agonists to stimulate GLP-2 secretion and intestinal adaptation in a piglet short-bowel model. In , parenterally fed neonatal pigs ( = 6/group) were gavaged with vehicle, olive extract (OE; 10 or 50 mg/kg), or ursolic acid (UA; 10 mg/kg), and plasma GLP-2 was measured for 6 h. In , neonatal pigs ( = 6-8/group) were subjected to transection or 80% mid-small intestine resection and, after 2 days, assigned to treatments for 10 days as follows: ) transection + vehicle (sham), ) resection + vehicle (SBS), ) resection + 30 mg UA (SBS + UA), and ) resection + 180 mg/kg OE (SBS + OE). We measured plasma GLP-2, intestinal histology, cell proliferation, and gene expression, as well as whole body citrulline-arginine kinetics and bile acid profiles. In , GLP-2 secretion was increased by UA and tended to be increased by OE. In , SBS alone, but not additional treatment with either TGR5 agonist, resulted in increased mucosal thickness and crypt cell proliferation in remnant jejunum and ileum sections. SBS increased biliary and ileal concentration of bile acids and expression of inflammatory and farnesoid X receptor target genes, but these measures were suppressed by UA treatment. In conclusion, UA is an effective oral GLP-2 secretagogue in parenterally fed pigs but is not capable of augmenting GLP-2 secretion or the intestinal adaptation response after massive small bowel resection. Therapeutic activation of endogenous glucagon-like peptide 2 (GLP-2) secretion is a promising strategy to improve intestinal adaptation in patients with short bowel syndrome. This study in neonatal pigs showed that oral supplementation with a selective Takeda G protein-coupled receptor 5 (TGR5) agonist is an effective approach to increase GLP-2 secretion. The results warrant further study to establish a more potent oral TGR5 agonist that can effectively improve intestinal adaptation in pediatric patients with SBS.

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TGR5-dependent hepatoprotection through the regulation of biliary epithelium barrier function.

We 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.

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