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https://www.readbyqxmd.com/read/28543567/tgr5-contributes-to-hepatic-cystogenesis-in-rodents-with-polycystic-liver-diseases-via-camp-g%C3%AE-s-signaling
#1
Tatyana V Masyuk, Anatoliy I Masyuk, Maria Lorenzo Pisarello, Brynn N Howard, Bing Q Huang, Pui-Yuen Lee, Xavier Fung, Eduard Sergienko, Robert J Ardesky, Thomas Dy Chung, Anthony B Pinkerton, Nicholas F LaRusso
Hepatic cystogenesis in Polycystic Liver Disease (PLD) is associated with increased levels of cAMP in cholangiocytes lining liver cysts. TGR5, a G protein-coupled bile acid receptor, is linked to cAMP and expressed in cholangiocytes. Therefore, we hypothesized that TGR5 might contribute to disease progression. We examined expression of TGR5 and Gα proteins in cultured cholangiocytes and in livers of animal models and humans with PLD. In vitro, we assessed cholangiocyte proliferation, cAMP levels, and cyst growth in response to: (i) TGR5 agonists [taurolithocholic acid (TLCA), oleanolic acid (OA) and two synthetic compounds]; (ii) a novel TGR5 antagonist (SBI-115); and (iii) a combination of SBI-115 and pasireotide, a somatostatin receptor (SSTR) analog...
May 23, 2017: Hepatology: Official Journal of the American Association for the Study of Liver Diseases
https://www.readbyqxmd.com/read/28523111/discovery-of-orally-efficacious-tetrahydrobenzimidazoles-as-tgr5-agonists-for-type-2-diabetes
#2
Xuqing Zhang, Mark Wall, Zhihua Sui, Jack Kauffman, Cuifen Hou, Cailin Chen, Fuyong Du, Thomas Kirchner, Yin Liang, Dana L Johnson, William V Murray, Keith Demarest
We have discovered a novel series of tetrahydrobenzimidazoles 3 as TGR5 agonists. Initial structure-activity relationship studies with an assay that measured cAMP levels in murine enteroendocrine cells (STC-1 cells) led to the discovery of potent agonists with submicromolar EC50 values for mTGR5. Subsequent optimization through methylation of the 7-position of the core tetrahydrobenzimidazole ring resulted in the identification of potent agonists for both mTGR5 and hTGR5 (human enteroendocrine NCI-H716 cells)...
May 11, 2017: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28514728/the-g-protein-coupled-bile-acid-receptor-gpbar1-tgr5-protects-against-renal-inflammation-and-renal-cancer-cell-proliferation-and-migration-through-antagonizing-nf-%C3%AE%C2%BAb-and-stat3-signaling-pathways
#3
Jia Su, Qiqi Zhang, Hui Qi, Linlin Wu, Yuanqiang Li, Donna Yu, Wendong Huang, Wei-Dong Chen, Yan-Dong Wang
Gpbar1 (TGR5), a G-protein-coupled bile acid membrane receptor, is well known for its roles in regulation of glucose metabolism and energy homeostasis. In the current work, we found that TGR5 activation by its ligand suppressed lipopolysaccharide (LPS)-induced proinflammatory gene expression in wild-type (WT) but not TGR5-/- mouse kidney. Furthermore, we found that TGR5 is a suppressor of kidney cancer cell proliferation and migration. We show that TGR5 activation antagonized NF-κB and STAT3 signaling pathways through suppressing the phosphorylation of IκBα, the translocation of p65 and the phosphorylation of STAT3...
April 29, 2017: Oncotarget
https://www.readbyqxmd.com/read/28511935/bile-acids-and-male-fertility-from-mouse-to-human
#4
REVIEW
Lauriane Sèdes, Emmanuelle Martinot, Marine Baptissart, Silvère Baron, Françoise Caira, Claude Beaudoin, David H Volle
Next to their involvement in digestion, bile acids have been defined as signaling molecules. They have been demonstrated to control many physiological functions among which lipid homeostasis, glucose and energy metabolisms. Bile acids are ligands of several receptors and multiple studies using transgenic mouse models defined the major roles of their respective nuclear and membrane receptors namely the Farnesoid-X-Receptor (FXRα) and the G-protein-coupled bile acid receptor 1(GPBAR1; TGR5). Here we review the reports highlighting the impacts of bile acids on testicular physiology and on male reproductive functions...
May 16, 2017: Molecular Aspects of Medicine
https://www.readbyqxmd.com/read/28446062/metabolite-sensing-g-protein-coupled-receptors-facilitators-of-diet-related-immune-regulation
#5
Jian K Tan, Craig McKenzie, Eliana Mariño, Laurence Macia, Charles R Mackay
Nutrition and the gut microbiome regulate many systems, including the immune, metabolic, and nervous systems. We propose that the host responds to deficiency (or sufficiency) of dietary and bacterial metabolites in a dynamic way, to optimize responses and survival. A family of G protein-coupled receptors (GPCRs) termed the metabolite-sensing GPCRs bind to various metabolites and transmit signals that are important for proper immune and metabolic functions. Members of this family include GPR43, GPR41, GPR109A, GPR120, GPR40, GPR84, GPR35, and GPR91...
April 26, 2017: Annual Review of Immunology
https://www.readbyqxmd.com/read/28435224/investigation-of-triamterene-as-an-inhibitor-of-the-tgr5-receptor-identification-in-cells-and-animals
#6
Yingxiao Li, Kai Chun Cheng, Chiang-Shan Niu, Shih-Hsiang Lo, Juei-Tang Cheng, Ho-Shan Niu
BACKGROUND: G-protein-coupled bile acid receptor 1 (GPBAR1, also known as TGR5) has been shown to participate in glucose homeostasis. In animal models, a TGR5 agonist increases incretin secretion to reduce hyperglycemia. Many agonists have been developed for clinical use. However, the effects of TGR5 blockade have not been studied extensively, with the exception of studies using TGR5 knockout mice. Therefore, we investigated the potential effect of triamterene on TGR5. METHODS: We transfected the TGR5 gene into cultured Chinese hamster ovary cells (CHO-K1 cells) to express TGR5...
2017: Drug Design, Development and Therapy
https://www.readbyqxmd.com/read/28422755/%C3%AE-klotho-deficiency-protects-against-obesity-through-a-crosstalk-between-liver-microbiota-and-brown-adipose-tissue
#7
Emmanuel Somm, Hugues Henry, Stephen J Bruce, Sébastien Aeby, Marta Rosikiewicz, Gerasimos P Sykiotis, Mohammed Asrih, François R Jornayvaz, Pierre Damien Denechaud, Urs Albrecht, Moosa Mohammadi, Andrew Dwyer, James S Acierno, Kristina Schoonjans, Lluis Fajas, Gilbert Greub, Nelly Pitteloud
β-Klotho (encoded by Klb) is the obligate coreceptor mediating FGF21 and FGF15/19 signaling. Klb-/- mice are refractory to beneficial action of pharmacological FGF21 treatment including stimulation of glucose utilization and thermogenesis. Here, we investigated the energy homeostasis in Klb-/- mice on high-fat diet in order to better understand the consequences of abrogating both endogenous FGF15/19 and FGF21 signaling during caloric overload. Surprisingly, Klb-/- mice are resistant to diet-induced obesity (DIO) owing to enhanced energy expenditure and BAT activity...
April 20, 2017: JCI Insight
https://www.readbyqxmd.com/read/28414465/topical-intestinal-aminoimidazole-agonists-of-g-protein-coupled-bile-acid-receptor-1-promote-glucagon-like-peptide-1-secretion-and-improve-glucose-tolerance
#8
Manuel Lasalle, Vanessa Hoguet, Nathalie Hennuyer, Florence Leroux, Catherine Piveteau, Loïc Belloy, Sophie Lestavel, Emmanuelle Vallez, Emilie Dorchies, Isabelle Duplan, Emmanuel Sevin, Maxime Culot, Fabien Gosselet, Rajaa Boulahjar, Adrien Herledan, Bart Staels, Benoit Deprez, Anne Tailleux, Julie Charton
The role of the G-protein-coupled bile acid receptor TGR5 in various organs, tissues, and cell types, specifically in intestinal endocrine L-cells and brown adipose tissue, has made it a promising therapeutical target in several diseases, especially type-2 diabetes and metabolic syndrome. However, recent studies have shown deleterious on-target effects of systemic TGR5 agonists. To avoid these systemic effects while stimulating glucagon-like peptide-1 (GLP-1) secreting enteroendocrine L-cells, we have designed TGR5 agonists with low intestinal permeability...
May 5, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28390813/bile-acids-and-bariatric-surgery
#9
REVIEW
Vance L Albaugh, Babak Banan, Hana Ajouz, Naji N Abumrad, Charles R Flynn
Bariatric surgery, specifically Roux-en-Y gastric bypass (RYGB) and vertical sleeve gastrectomy (VSG), are the most effective and durable treatments for morbid obesity and potentially a viable treatment for type 2 diabetes (T2D). The resolution rate of T2D following these procedures is between 40 and 80% and far surpasses that achieved by medical management alone. The molecular basis for this improvement is not entirely understood, but has been attributed in part to the altered enterohepatic circulation of bile acids...
April 17, 2017: Molecular Aspects of Medicine
https://www.readbyqxmd.com/read/28381740/the-associations-between-circulating-bile-acids-and-the-muscle-volume-in-patients-with-non-alcoholic-fatty-liver-disease-nafld
#10
Yoshinao Kobayashi, Nagisa Hara, Ryosuke Sugimoto, Rumi Mifuji-Moroka, Hideaki Tanaka, Akiko Eguchi, Motoh Iwasa, Hiroshi Hasegawa, Kazuko Iwata, Yoshiyuki Takei, Osamu Taguchi
Objective Non-alcoholic fatty liver disease (NAFLD) is frequently associated with obesity, dyslipidemia and type-2 diabetes mellitus. Bile acids (BAs) bind to the farnesoid X receptor (FXR) and G protein-coupled receptor 5 (TGR5), which are involved in lipid and glucose metabolism and energy expenditure. The present study aimed to determine associations between the circulating BAs and the skeletal muscle volume (SMV), and lipid and glucose metabolism in patients with NAFLD. Methods Serum BAs and metabolic parameters were measured in 55 patients with NAFLD (median age, 55 years)...
2017: Internal Medicine
https://www.readbyqxmd.com/read/28370265/zizyphin-modulates-calcium-signalling-in-human-taste-bud-cells-and-fat-taste-perception-in-the-mouse
#11
Babar Murtaza, Meryem Berrichi, Chahid Bennamar, Thierry Tordjmann, Fatima Z Djeziri, Aziz Hichami, Julia Leemput, Meriem Belarbi, Hakan Ozdener, Naim A Khan
Zizyphin, isolated from Zizyphus sps. leaf extracts, has been shown to modulate sugar taste perception, and the palatability of a sweet solution is increased by the addition of fatty acids. We, therefore, studied whether zizyphin also modulates fat taste perception. Zizyphin was purified from edible fruit of Zizyphus lotus L. Zizyphin-induced increases in [Ca(2+) ]i in human taste bud cells (hTBC). Zizyphin shared the endoplasmic reticulum Ca(2+) pool and also recruited, in part, Ca(2+) from extracellular environment via the opening of store-operated Ca(2+) channels...
April 2, 2017: Fundamental & Clinical Pharmacology
https://www.readbyqxmd.com/read/28324023/long-chain-free-fatty-acid-receptor-gpr120-mediates-oil-induced-gip-secretion-through-cck-in-male-mice
#12
Akiko Sankoda, Norio Harada, Kanako Iwasaki, Shunsuke Yamane, Yuki Murata, Kimitaka Shibue, Yotsapon Thewjitcharoen, Kazuyo Suzuki, Takanari Harada, Yoshinori Kanemaru, Satoko Shimazu-Kuwahara, Akira Hirasawa, Nobuya Inagaki
Free fatty acid receptors GPR120 and GPR40 are involved in the secretion of gut hormones. GPR120 and GPR40 are expressed in enteroendocrine K-cells and their activation induces the secretion of the incretin glucose-dependent insulinotropic polypeptide (GIP). However, the role of these receptors in fat-induced GIP secretion in vivo and the associated mechanisms are unclear. In this study, we investigated corn oil-induced GIP secretion in GPR120-knockout (GPR120-/-) and GPR40-knockout (GPR40-/-) mice. Oil-induced GIP secretion was reduced by 50% and 80% in GPR120-/- and GPR40-/- mice compared to that in wild-type (WT) mice, respectively...
March 15, 2017: Endocrinology
https://www.readbyqxmd.com/read/28304141/evidence-connecting-old-new-and-neglected-glucose-lowering-drugs-to-bile-acid-induced-glp-1-secretion-a-review
#13
REVIEW
Martin L Kårhus, Andreas Brønden, David P Sonne, Tina Vilsbøll, Fillip K Knop
Bile acids are amphipathic water-soluble steroid-based molecules best known for their important lipid-solubilizing role in the assimilation of fat. Recently, bile acids have emerged as metabolic integrators with glucose-lowering potential. Among a variety of gluco-metabolic effects, bile acids have been demonstrated to modulate the secretion of the gut-derived incretin hormone glucagon-like peptide-1 (GLP-1), possibly via the transmembrane receptor Takeda G-protein-coupled receptor 5 and the nuclear farnesoid X receptor, in intestinal L cells...
March 17, 2017: Diabetes, Obesity & Metabolism
https://www.readbyqxmd.com/read/28302491/bile-acids-and-their-receptors-during-liver-regeneration-dangerous-protectors
#14
REVIEW
Grégory Merlen, José Ursic-Bedoya, Valeska Jourdainne, Nicolas Kahale, Mathilde Glenisson, Isabelle Doignon, Dominique Rainteau, Thierry Tordjmann
Tissue repair is orchestrated by a finely tuned interplay between processes of regeneration, inflammation and cell protection, allowing organisms to restore their integrity after partial loss of cells or organs. An important, although largely unexplored feature is that after injury and during liver repair, liver functions have to be maintained to fulfill the peripheral demand. This is particularly critical for bile secretion, which has to be finely modulated in order to preserve liver parenchyma from bile-induced injury...
March 23, 2017: Molecular Aspects of Medicine
https://www.readbyqxmd.com/read/28293080/tgr5-expression-in-benign-preneoplastic-and-neoplastic-lesions-of-barrett-s-esophagus-case-series-and-findings
#15
Shivali Marketkar, Dan Li, Dongfang Yang, Weibiao Cao
AIM: To examined the bile acid receptor TGR5 expression in squamous mucosa, Barrett's mucosa, dysplasia and esophageal adenocarcinoma (EA). METHODS: Slides were stained with TGR5 antibody. The staining intensity was scored as 1+, 2+ and 3+. The extent of staining (percentage of cells staining) was scored as follows: 1+, 1%-10%, 2+, 11%-50%, 3+, 51%-100%. A combined score of intensity and extent was calculated and categorized as negative, weak, moderate and strong staining...
February 28, 2017: World Journal of Gastroenterology: WJG
https://www.readbyqxmd.com/read/28285911/evaluation-of-anti-diabetic-effect-and-gall-bladder-function-with-2-thio-5-thiomethyl-substituted-imidazoles-as-tgr5-receptor-agonists
#16
Xuqing Zhang, Zhihua Sui, Jack Kauffman, Cuifen Hou, Cailin Chen, Fuyong Du, Thomas Kirchner, Yin Liang, Dana Johnson, William V Murray, Keith Demarest
A novel series of 2-thio-5-thiomethyl substituted imidazoles was discovered to be potent TGR5 agonists that possessed glucose-lowering effects while inhibiting gall bladder emptying in mice.
February 28, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28249291/bile-acid-uptake-transporters-as-targets-for-therapy
#17
REVIEW
Davor Slijepcevic, Stan F J van de Graaf
Bile acids are potent signaling molecules that regulate glucose, lipid and energy homeostasis predominantly via the bile acid receptors farnesoid X receptor (FXR) and transmembrane G protein-coupled receptor 5 (TGR5). The sodium taurocholate cotransporting polypeptide (NTCP) and the apical sodium dependent bile acid transporter (ASBT) ensure an effective circulation of (conjugated) bile acids. The modulation of these transport proteins affects bile acid localization, dynamics and signaling. The NTCP-specific pharmacological inhibitor myrcludex B inhibits hepatic uptake of conjugated bile acids...
2017: Digestive Diseases
https://www.readbyqxmd.com/read/28249284/disease-associated-changes-in-bile-acid-profiles-and-links-to-altered-gut-microbiota
#18
REVIEW
Susan A Joyce, Cormac G M Gahan
The gastrointestinal microbiota plays a central role in the host metabolism of bile acids through deconjugation and dehydroxylation reactions, which generate unconjugated free bile acids and secondary bile acids respectively. These microbially generated bile acids are particularly potent signalling molecules that interact with host bile acid receptors (including the farnesoid X receptor, vitamin D receptor and TGR5 receptor) to trigger cellular responses that play essential roles in host lipid metabolism, electrolyte transport and immune regulation...
2017: Digestive Diseases
https://www.readbyqxmd.com/read/28249273/intestinal-farnesoid-x-receptor-and-takeda-g-protein-couple-receptor-5-signaling-in-metabolic-regulation
#19
REVIEW
John Y L Chiang, Preeti Pathak, Hailiang Liu, Ajay Donepudi, Jessica Ferrell, Shannon Boehme
Bile acids play a critical role in the regulation of glucose, lipid and energy metabolisms by activating the nuclear bile acid receptor farnesoid X receptor (FXR) and membrane G protein-coupled bile acid receptor-1 (aka takeda G protein couple receptor 5, TGR5) signaling. Paradoxical roles of FXR in the regulation of glucose and lipid metabolism and metabolic disorder have been reported recently. The activation or inhibition of intestinal FXR signaling has been shown to improve insulin and glucose sensitivity and energy metabolism to prevent diabetes, obesity and non-alcoholic fatty liver disease (NAFLD)...
2017: Digestive Diseases
https://www.readbyqxmd.com/read/28249265/role-of-the-g-protein-coupled-bile-acid-receptor-tgr5-in-liver-damage
#20
REVIEW
Maria Reich, Caroline Klindt, Kathleen Deutschmann, Lina Spomer, Dieter Häussinger, Verena Keitel
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...
2017: Digestive Diseases
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