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Differential Action of TGR5 Agonists on GLP-2 Secretion and Promotion of Intestinal Adaptation in Piglet Short Bowel Model.

Enteroendocrine L cells and GLP-2 secretion are activated in the intestinal adaptation process following bowel resection in short bowel patients. Our aim was to assess whether 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 in a piglet model. In study 1, parenterally-fed, neonatal pigs (n=6/group) were gavaged with vehicle, olive extract (OE) at 10 or 50 mg/kg, or ursolic acid (UA) 10 mg/kg and plasma GLP-2 were measured for 6 hr. In study 2, neonatal pigs (n=6-8/group) received either transection or 80% mid-small intestine resection and after 2 d assigned to treatments for 10 d including: 1) transection + vehicle (Sham), 2) resection + vehicle (SBS), 3) resection + (30 mg UA)(SBS-UA), 4) resection + (180 mg/kg OE)(SBS-OE). We measured plasma GLP-2, intestinal histology, cell proliferation, gene expression as well as whole body citrulline-arginine kinetics and bile acid profiles. In study 1, GLP-2 secretion was increased by UA and tended be with OE. In study 2, 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 FXR-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 was not capable of augmenting GLP-2 secretion nor the intestinal adaptation response after massive small bowel resection.

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TGR5 agonist INT-777 mitigates inflammatory response in human endometriotic stromal cells: A therapeutic implication for endometriosis.

Endometriosis is a condition characterized by the presence of endometrial tissues outside the uterus. Endometriotic stromal cells (ESCs) are known to undergo regeneration and are linked to the causation of endometriosis. Activation of stromal cells by local inflammatory cytokines is proposed to be one of the mechanisms of endometriosis development. Takeda-G-protein-receptor-5 (TGR5) is a G protein-coupled bile acid receptor that plays multiple roles in various cells and tissues. In this study, we show that activation of TGR5 by its specific agonist, INT-777, protects ESCs from inflammation and oxidative stress induced by tumor necrosis factor-α (TNF-α). TGR5 is fairly expressed in cultured ESCs, and TNF-α treatment suppresses TGR5 expression. Activation of TGR5 by its synthetic agonist, INT-777, dramatically reduces the production of pro-inflammatory cytokines and adhesion molecules by TNF-α, including interleukin-6 (IL-6), interleukin-8 (IL-8), monocyte chemoattractant protein-1 (MCP-1), intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1). Moreover, INT-777 suppresses TNF-α-induced NADPH oxidase 4 (NOX4) expression and ameliorates cellular oxidative stress. Mechanistically, our findings demonstrate that INT-777 suppresses TNF-α-induced c-Jun N-terminal kinase (JNK) activation via suppression of p-JNK. INT-777 inhibits TNF-α-induced activation of the activator protein-1 (AP-1) pathway owing to its suppression of c-Jun and c-fos as well as transfected AP-1 promoter. INT-777 also inhibits nuclear factor-κB (NF-κB) activation as revealed by its suppression of TNF-α-induced nuclear p65 accumulation and NF-κB promoter. Collectively, our data indicate that activation of TGR5 by its agonist has protective effects against inflammation and reactive oxygen species (ROS) in cytokine-induced activation of ESCs. Therefore, INT-777 may have an implication in the clinical treatment of endometriosis.

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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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Bile acids increase steroidogenesis in cholemic mice and induce cortisol secretion in adrenocortical H295R cells via S1PR2, ERK and SF-1.

Bile acids are now accepted as central signalling molecules for the regulation of glucose, amino acid and lipid metabolism. Adrenal gland cortex cells express the bile acid receptors farnesoid X receptor (FXR), the G protein-coupled bile acid receptor (TGR5) and the sphingosine-1-phosphate receptor 2 (S1PR2). We aimed to determine the effects of cholestasis and more specifically of bile acids on cortisol production.

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Lysophosphatidic acid activates satellite glia cells and Schwann cells.

Pruritus is a common and disabling symptom in patients with hepatobiliary disorders, particularly in those with cholestatic features. Serum levels of lysophosphatidic acid (LPA) and its forming enzyme autotaxin were increased in patients suffering from hepatic pruritus, correlated with itch severity and response to treatment. Here we show that in a culture of dorsal root ganglia LPA 18:1 surprisingly activated a large fraction of satellite glia cells, and responses to LPA 18:1 correlated inversely with responses to neuronal expressed transient receptor potential channels. LPA 18:1 caused only a marginal activation of heterologously expressed TRPV1, and responses in dorsal root ganglion cultures from TRPV1-deficient mice were similar to controls. LPA 18:1 desensitized subsequent responsiveness to chloroquine and TGR5 agonist INT-777. The LPA 18:1-induced increase in cytoplasmatic calcium stems from the endoplasmatic reticulum. LPA receptor expression in dorsal root ganglia and Schwann cells, LPAR1 immunohistochemistry, and pharmacological results indicate a signaling pathway through LPA receptor 1. Peripheral rat Schwann cells, which are of glial lineage as the satellite glia cells, were also responsive to LPA 18:1. Summarizing, LPA 18:1 primarily activates rather glial cells than neurons, which may subsequently modulate neuronal responsiveness and sensory sensations such as itch and pain.

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Intestinal TGR5 agonism improves hepatic steatosis and insulin sensitivity in Western diet-fed mice.

Takeda G protein-coupled receptor 5 (TGR5) agonists induce systemic release of glucagon-like peptides (GLPs) from intestinal L cells, a potentially therapeutic action against metabolic diseases such as nonalcoholic steatohepatitis (NASH), nonalcoholic fatty liver disease (NAFLD), and Type 2 diabetes. Historically, TGR5 agonist use has been hindered by side effects, including inhibition of gallbladder emptying. Here, we characterize RDX8940, a novel, orally administered TGR5 agonist designed to have minimal systemic effects and investigate its activity in mice fed a Western diet, a model of NAFLD and mild insulin resistance. Agonist activity, binding selectivity, toxicity, solubility, and permeability of RDX8940 were characterized in standard in vitro models. RDX8940 pharmacokinetics and effects on GLP secretion, insulin sensitivity, and liver steatosis were assessed in C57BL/6 mice fed normal or Western diet chow and given single or repeated doses of RDX8940 or vehicle, with or without dipeptidyl peptidase-4 (DPP4) inhibitors. Gallbladder effects were assessed in CD-1 mice fed normal chow and given RDX8940 or a systemic TGR5 agonist or vehicle. Our results showed that RDX8940 is minimally systemic, potent, and selective, and induces incretin (GLP-1, GLP-2, and peptide YY) secretion. RDX8940-induced increases in plasma active GLP-1 (aGLP-1) levels were enhanced by repeated dosing and by coadministration of DPP4 inhibitors. RDX8940 increased hepatic exposure to aGLP-1 without requiring coadministration of a DPP4 inhibitor. In mice fed a Western diet, RDX8940 improved liver steatosis and insulin sensitivity. Unlike systemic TGR5 agonists, RDX8940 did not inhibit gallbladder emptying. These results indicate that RDX8940 may have therapeutic potential in patients with NAFLD/NASH. NEW & NOTEWORTHY Takeda G protein-coupled receptor 5 (TGR5) agonists have potential as a treatment for nonalcoholic steatohepatitis and nonalcoholic fatty liver disease (NAFLD) but have until now been associated with undesirable side effects associated with systemic TGR5 agonism, including blockade of gallbladder emptying. We demonstrate that RDX8940, a potent, selective, minimally systemic oral TGR5 agonist, improves liver steatosis and insulin sensitivity in a mouse model of NAFLD and does not inhibit gallbladder emptying in mice.

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Developments in bile salt based therapies: A critical overview.

Bile acids, amphipathic molecules known for their facilitating role in fat absorption, are also recognized as signalling molecules acting via nuclear and membrane receptors. Of the bile acid-activated receptors, the Farnesoid X Receptor (FXR) and the G protein-coupled bile acid receptor-1 (Gpbar1 or TGR5) have been studied most extensively. Bile acid signaling is critical in the regulation of bile acid metabolism itself, but it also plays a significant role in glucose, lipid and energy metabolism. Activation of FXR and TGR5 leads to reduced hepatic bile salt load, improved insulin sensitivity and glucose regulation, increased energy expenditure, and anti-inflammatory effects. These beneficial effects render bile acid signaling an interesting therapeutic target for the treatment of diseases such as cholestasis, non-alcoholic fatty liver disease, and diabetes. Here, we summarize recent findings on bile acid signaling and discuss potential and current limitations of bile acid receptor agonist and modulators of bile acid transport as future therapeutics for a wide-spectrum of diseases.

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Dual Targeting of Bile Acid Receptor-1 (TGR5) and Farnesoid X Receptor (FXR) Prevents Estrogen-Dependent Bone Loss in Mice.

Osteoporosis is a global bone disease characterized by reduced bone mineral density (BMD) and increased risk of fractures. The risk of developing osteoporosis increases with aging, especially after menopause in women. Discovering the signaling pathways that play a significant role in aging- and menopause-induced osteoporosis should accelerate osteoporosis drug discovery. In this study, we found that bile acid membrane receptor Tgr5 knockout C57BL/6J mice had similar bone mass as wild-type mice during early and middle-age (before 4 months old) bone remodeling; however, Tgr5 markedly decreased bone mass in aged (more than 7 months old) and ovariectomized (OVX) mice compared with wild-type mice. Moreover, Tgr5 knockout strongly induced osteoclast differentiation but had no effect on osteoblast activity. Treatment with different TGR5 agonists consistently inhibited osteoclast differentiation. Importantly, our results showed that Tgr5 regulates osteoclastogenesis by the AMP-activated protein kinase (AMPK) signaling pathway, which is a central metabolic pathway involved in the pathophysiology of aging and age-related diseases. The bile acid nuclear receptor FXR is an established regulator of bone metabolism. We screened the derivatives of betulinic acid (BA), a known TGR5 agonist, to identify novel dual agonists of FXR and TGR5. The derivative SH-479, a pentacyclic triterpene acid, could activate both TGR5 and FXR, with a better inhibitory effect on osteoclastogenesis compared with agonists solely activating FXR or TGR5 and additionally enhanced osteoblastogenesis. Furthermore, SH-479 therapeutically abrogated bone loss in C57BL/6J mice through the bone remodeling pathways. Together, our results demonstrate that dual targeting the bile acid membrane receptor TGR5 and nuclear receptor FXR is a promising strategy for osteoporosis. © 2018 American Society for Bone and Mineral Research.

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FXR and TGR5 Agonists Ameliorate Liver Injury, Steatosis, and Inflammation After Binge or Prolonged Alcohol Feeding in Mice.

Bile acids (BAs) activate various dedicated receptors, including the farnesoid X receptor (FXR) and the Takeda G protein-coupled receptor 5 (TGR5). The FXR agonist obeticholic acid (OCA) is licensed for the treatment of primary biliary cholangitis and has shown promising results in NASH patients, whereas TGR5 agonists target inflammation and metabolism. We hypothesized that FXR and/or TGR5 agonists may be therapeutic in early alcoholic liver disease (ALD) in mice, in which hepatic inflammation plays a major role. OCA, INT-777, and INT-767 are BA derivatives with selective agonist properties for FXR, TGR5, or both, respectively. These compounds were tested in two mouse models (3-day binge model and prolonged Lieber DeCarli diet for 12 days) of early ALD. Serum alanine aminotransferase and liver histology were used to assess liver injury, Oil Red O staining of liver sections to assess steatosis, and real-time polymerase chain reaction to assess changes in gene expression. In the ethanol binge model, treatment with OCA and INT-777 decreased hepatic macrovesicular steatosis and protected from ethanol-induced liver injury. After prolonged ethanol administration, mice treated with OCA, INT-767, or INT-777 showed decreased hepatic steatosis, associated with reduced liver fatty acid synthase protein expression, and protection from liver injury. Treatment with BA receptor agonists in both models of ethanol administration modulated lipogenic gene expression, and decreased liver interleukin-1β mRNA expression associated with increased ubiquitination of NLRP3 inflammasome through cyclic adenosine monophosphate-induced activation of protein kinase A. OCA, INT-767, or INT-777 administration is effective in reducing acute and chronic ethanol-induced steatosis and inflammation in mice, with varying degrees of efficacy depending on the duration of ethanol administration, indicating that both FXR and TGR5 activation can protect from liver injury in ALD models.

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Activation of TGR5 promotes osteoblastic cell differentiation and mineralization.

Impairment of normal osteoblast differentiation has been associated with bone loss-related disorders, such as osteoporosis. Takeda G-protein coupled receptor 5 (TGR5) has been identified as an important modulator of bile acid and energy homeostasis. Little information regarding the effects of TGR5 on osteoblastic bone formation and matrix mineralization has been reported before. In the current study, we found that TGR5 was expressed in osteoblast-like cell line MC3T3-E1 cells. Osteogenic medium (OM) stimulation promoted the expression of TGR5 in a dose-dependent manner. Notably, treatment with the specific TGR5 agonist GPBARA increased ALP activity, matrix mineralization, and expressions of osteoblastic differentiation marker genes, such as ALP, OCN, and Osx, by promoting the expression of Runx-2. Silencing of TGR5 by transfection with TGR5 siRNA abolished these effects. Also, we found that the AMPK/eNOS pathway was involved in this process. Blockage of AMPK activation using its specific inhibitor compound C abolished the effect of GPBARA-induced increase in ALP activity, matrix mineralization, and expressions of osteoblastic differentiation marker genes. The obtained results provide a new insight into the physiological function of TGR5 in bone formation and suggest that TGR5 might be a novel therapeutic target for bone diseases.

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