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https://www.readbyqxmd.com/read/27924062/chenodeoxycholic-acid-activates-nlrp3-inflammasome-and-contributes-to-cholestatic-liver-fibrosis
#1
Zizhen Gong, Jiefei Zhou, Shengnan Zhao, Chunyan Tian, Panliang Wang, Congfeng Xu, Yingwei Chen, Wei Cai, Jin Wu
Accumulation of hydrophobic bile acids in the liver contributes to cholestatic liver injury. Inflammation induced by excessive bile acids is believed to play a crucial role, however, the mechanisms of bile acids triggered inflammatory response remain unclear. Recent studies have highlighted the effect of NLRP3 inflammasome in mediating liver inflammation and fibrosis. In this study, we for the first time showed that chenodeoxycholic acid (CDCA), the major hydrophobic primary bile acid involved in cholestatic liver injury, could dose-dependently induce NLRP3 inflammasome activation and secretion of pro-inflammatory cytokine-IL-1β in macrophages by promoting ROS production and K+ efflux...
December 4, 2016: Oncotarget
https://www.readbyqxmd.com/read/27908836/gq-and-gs-signaling-acting-in-synergy-to-control-glp-1-secretion
#2
Maria Hauge, Jeppe Pio Ekberg, Maja Storm Engelstoft, Pascal Timshel, Andreas N Madsen, Thue W Schwartz
GPR40 is generally known to signal through Gq. However, in transfected cells, certain synthetic agonists can make the receptor signal also through Gs and cAMP (Hauge et al., 2015). Here we find that, in colonic crypt cultures, the GLP-1 secretion induced by such Gq + Gs GPR40 agonists is indeed inhibited by blockers of both Gq and Gs and is eliminated by combining these. This in contrast to Gq-only GPR40 agonists which only are affected by the Gq inhibitor. Importantly, Gq-only GPR40 agonists in combination with low doses of selective synthetic agonists for Gs coupled receptors, e...
November 28, 2016: Molecular and Cellular Endocrinology
https://www.readbyqxmd.com/read/27846919/intestinal-bile-acid-receptors-are-key-regulators-of-glucose-homeostasis
#3
Mohamed-Sami Trabelsi, Sophie Lestavel, Bart Staels, Xavier Collet
In addition to their well-known function as dietary lipid detergents, bile acids have emerged as important signalling molecules that regulate energy homeostasis. Recent studies have highlighted that disrupted bile acid metabolism is associated with metabolism disorders such as dyslipidaemia, intestinal chronic inflammatory diseases and obesity. In particular, type 2 diabetes (T2D) is associated with quantitative and qualitative modifications in bile acid metabolism. Bile acids bind and modulate the activity of transmembrane and nuclear receptors (NR)...
November 16, 2016: Proceedings of the Nutrition Society
https://www.readbyqxmd.com/read/27833095/structural-assemblies-of-the-di-and-oligomeric-g-protein-coupled-receptor-tgr5-in-live-cells-an-mfis-fret-and-integrative-modelling-study
#4
Annemarie Greife, Suren Felekyan, Qijun Ma, Christoph G W Gertzen, Lina Spomer, Mykola Dimura, Thomas O Peulen, Christina Wöhler, Dieter Häussinger, Holger Gohlke, Verena Keitel, Claus A M Seidel
TGR5 is the first identified bile acid-sensing G-protein coupled receptor, which has emerged as a potential therapeutic target for metabolic disorders. So far, structural and multimerization properties are largely unknown for TGR5. We used a combined strategy applying cellular biology, Multiparameter Image Fluorescence Spectroscopy (MFIS) for quantitative FRET analysis, and integrative modelling to obtain structural information about dimerization and higher-order oligomerization assemblies of TGR5 wildtype (wt) and Y111 variants fused to fluorescent proteins...
November 11, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27808040/endobarrier-gastrointestinal-liner-delineation-of-underlying-mechanisms-and-clinical-effects
#5
Ulrich Rohde
Bariatric surgery (e.g. Roux-en-Y gastric bypass (RYGB)) has proven the most effective way of achieving sustainable weight losses and remission of type 2 diabetes (T2D). Studies indicate that the effectiveness of RYGB is mediated by an altered gastrointestinal tract anatomy, which in particular favours release of the gut incretin hormone glucagon-like peptide-1 (GLP-1). The EndoBarrier gastrointestinal liner or duodenal-jejunal bypass sleeve (DJBS) is an endoscopic deployable minimally invasive and fully reversible technique designed to mimic the bypass component of the RYGB...
November 2016: Danish Medical Journal
https://www.readbyqxmd.com/read/27789682/disrupted-murine-gut-to-human-liver-signaling-alters-bile-acid-homeostasis-in-humanized-mouse-liver-models
#6
Edwin C Y Chow, Holly P Quach, Yueping Zhang, Jason Z Y Wang, David C Evan, Albert P Li, Jose Silva, Rommel G Tirona, Yurong Lai, K Sandy Pang
The humanized liver mouse model is increasingly being exploited for human drug metabolism studies. However, its model stability, inter-communication between human hepatocytes and mouse non-parenchymal cells in liver and murine intestine, and changes in extrahepatic transporter and enzyme expression has not been investigated. We examined these issues in FRGN [Fah(-/-), Rag2(-/-), and IL-2rg(-/-) on NOD background] and chimeric mice: mFRGN, and hFRGN (repopulated with mouse or human hepatocytes, respectively)...
October 27, 2016: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/27775551/antibiotic-effects-on-gut-microbiota-and-metabolism-are-host-dependent
#7
Shiho Fujisaka, Siegfried Ussar, Clary Clish, Suzanne Devkota, Jonathan M Dreyfuss, Masaji Sakaguchi, Marion Soto, Masahiro Konishi, Samir Softic, Emrah Altindis, Ning Li, Georg Gerber, Lynn Bry, C Ronald Kahn
Interactions of diet, gut microbiota, and host genetics play important roles in the development of obesity and insulin resistance. Here, we have investigated the molecular links between gut microbiota, insulin resistance, and glucose metabolism in 3 inbred mouse strains with differing susceptibilities to metabolic syndrome using diet and antibiotic treatment. Antibiotic treatment altered intestinal microbiota, decreased tissue inflammation, improved insulin signaling in basal and stimulated states, and improved glucose metabolism in obesity- and diabetes-prone C57BL/6J mice on a high-fat diet (HFD)...
December 1, 2016: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/27765751/decoding-the-vasoregulatory-activities-of-bile-acid-activated-receptors-in-systemic-and-portal-circulation-role-for-gaseous-mediators
#8
Stefano Fiorucci, Angela Zampella, Giuseppe Cirino, Mariarosaria Bucci, Eleonora Distrutti
Bile acids are end product of cholesterol metabolism generated in the liver and released in the intestine. In addition to their role in nutrient absorption, bile acids are increasingly recognized as regulatory signals which exert their function beyond the intestine by activating a network of membrane and nuclear receptors. The best characterized of these bile acid activated receptors, GPBAR1 (also known as TGR5) and the Farnesosid-x-receptor (FXR) have also been detected in the vascular system and their activation mediate the vasodilatory effects of bile acids in the systemic and splanchnic circulation...
October 7, 2016: American Journal of Physiology. Heart and Circulatory Physiology
https://www.readbyqxmd.com/read/27692610/bile-acids-control-inflammation-and-metabolic-disorder-through-inhibition-of-nlrp3-inflammasome
#9
Chuansheng Guo, Shujun Xie, Zhexu Chi, Jinhua Zhang, Yangyang Liu, Li Zhang, Mingzhu Zheng, Xue Zhang, Dajing Xia, Yuehai Ke, Linrong Lu, Di Wang
Reciprocal interactions between the metabolic system and immune cells play pivotal roles in diverse inflammatory diseases, but the underlying mechanisms remain elusive. The activation of bile acid-mediated signaling has been linked to improvement in metabolic syndromes and enhanced control of inflammation. Here, we demonstrated that bile acids inhibited NLRP3 inflammasome activation via the TGR5-cAMP-PKA axis. TGR5 bile acid receptor-induced PKA kinase activation led to the ubiquitination of NLRP3, which was associated with the PKA-induced phosphorylation of NLRP3 on a single residue, Ser 291...
October 18, 2016: Immunity
https://www.readbyqxmd.com/read/27639537/clinical-relevance-of-the-bile-acid-receptor-tgr5-in-metabolism
#10
F Samuel van Nierop, Matthijs J Scheltema, Hannah M Eggink, Thijs W Pols, David P Sonne, Filip K Knop, Maarten R Soeters
The bile acid receptor TGR5 (also known as GPBAR1) is a promising target for the development of pharmacological interventions in metabolic diseases, including type 2 diabetes, obesity, and non-alcoholic steatohepatitis. TGR5 is expressed in many metabolically active tissues, but complex enterohepatic bile acid cycling limits the exposure of some of these tissues to the receptor ligand. Profound interspecies differences in the biology of bile acids and their receptors in different cells and tissues exist. Data from preclinical studies show promising effects of targeting TGR5 on outcomes such as weight loss, glucose metabolism, energy expenditure, and suppression of inflammation...
September 14, 2016: Lancet Diabetes & Endocrinology
https://www.readbyqxmd.com/read/27597295/gpbar1-tgr5-attenuates-liver-ischemia-reperfusion-injury-via-the-inhibition-of-tlr4-signaling-in-mice
#11
Haojun Yang, Haoming Zhou, Lin Zhuang, Xuehao Wang, Ling Lv
BACKGROUND: The G protein-coupled receptor TGR5 is a novel plasma membrane-bound G protein-coupled bile acid (BA) receptor. TGR5-induced liver protection has been demonstrated during several liver diseases, except during ischemia/reperfusion injury (IRI). METHOD: Male adult wild-type and TGR5 knockout mice were subjected to liver partial warm ischemia/reperfusion. Hepatic injury was evaluated based on serum alanine aminotransferase (ALT) and serum aspartate aminotransferase (AST)...
September 6, 2016: Liver Transplantation
https://www.readbyqxmd.com/read/27578964/development-of-betulinic-acid-as-an-agonist-of-tgr5-receptor-using-a-new-in-vitro-assay
#12
Shih-Hsiang Lo, Kai-Chung Cheng, Ying-Xiao Li, Chin-Hong Chang, Juei-Tang Cheng, Kung-Shing Lee
BACKGROUND: G-protein-coupled bile acid receptor 1, also known as TGR5 is known to be involved in glucose homeostasis. In animal models, treatment with a TGR5 agonist induces incretin secretion to reduce hyperglycemia. Betulinic acid, a triterpenoid present in the leaves of white birch, has been introduced as a selective TGR5 agonist. However, direct activation of TGR5 by betulinic acid has not yet been reported. METHODS: Transfection of TGR5 into cultured Chinese hamster ovary (CHO-K1) cells was performed to establish the presence of TGR5...
2016: Drug Design, Development and Therapy
https://www.readbyqxmd.com/read/27558159/chenodeoxycholic-acid-requires-activation-of-egfr-epac-and-ca2-to-stimulate-cftr-dependent-cl-secretion-in-human-colonic-t84-cells
#13
Jada C Domingue, Mei Ao, Jayashree Sarathy, Mrinalini C Rao
Bile acids are known to initiate intricate signaling events in a variety of tissues, primarily in the liver and gastrointestinal tract. Of the known bile acids, only the dihydroxy species, deoxycholic acid and chenodeoxycholic acid (CDCA), and their conjugates, activate processes that stimulate epithelial Cl(-) secretion. We have previously published that CDCA acts in a rapid manner to stimulate colonic ion secretion via protein kinase A (PKA)-mediated activation of the dominant Cl(-) channel, the cystic fibrosis transmembrane conductance regulator (CFTR) (AJP 305:C447-56, 2013); however, PKA signaling did not account for the entire CDCA response...
August 24, 2016: American Journal of Physiology. Cell Physiology
https://www.readbyqxmd.com/read/27534992/cholesterol-7%C3%AE-hydroxylase-protects-the-liver-from-inflammation-and-fibrosis-by-maintaining-cholesterol-homeostasis
#14
Hailiang Liu, Preeti Pathak, Shannon Boehme, John Y L Chiang
Cholesterol 7α-hydroxylase (CYP7A1) plays a critical role in control of bile acid and cholesterol homeostasis. Bile acids activate farnesoid X receptor (FXR) and Takeda G protein-coupled receptor 5 (TGR5) to regulate lipid, glucose, and energy metabolism. However, the role of bile acids in hepatic inflammation and fibrosis remains unclear. In this study, we showed that adenovirus-mediated overexpression of Cyp7a1 ameliorated lipopolysaccharide (LPS)-induced inflammatory cell infiltration and pro-inflammatory cytokine production in WT and TGR5-deficient (Tgr5(-/-)) mice, but not in FXR-deficient (Fxr(-/-)) mice, suggesting that bile acid signaling through FXR protects against hepatic inflammation...
October 2016: Journal of Lipid Research
https://www.readbyqxmd.com/read/27511066/bile-acid-receptor-tgr5-nadph-oxidase-nox5-s-and-creb-mediate-bile-acid-induced-dna-damage-in-barrett-s-esophageal-adenocarcinoma-cells
#15
Dan Li, Weibiao Cao
The mechanisms whereby bile acid reflux may accelerate the progression from Barrett's esophagus (BE) to esophageal adenocarcinoma (EA) are not fully understood. In this study we found that bile acid taurodeoxycholic acid (TDCA) significantly increased the tail moment (TM) and histone H2AX phosphorylation in FLO-1 EA cells, an increase which was significantly decreased by knockdown of TGR5. Overexpression of TGR5 significantly increased TDCA-induced TM increase and H2AX phosphorylation. In addition, NADPH oxidase inhibitor diphenylene iodonium significantly inhibited the TDCA-induced increase in TM and H2AX phosphorylation...
2016: Scientific Reports
https://www.readbyqxmd.com/read/27510297/membrane-bile-acid-receptor-tgr5-predicts-good-prognosis-in-ampullary-adenocarcinoma-patients-with-hyperbilirubinemia
#16
Min-Chan Chen, Yi-Ling Chen, Tzu-Wen Wang, Hui-Ping Hsu, Ming-Derg Lai
Bile acids are potential carcinogens in gastrointestinal cancer, and interact with nuclear and membrane receptors to initiate downstream signaling. The effect of TGR5 [also known as G protein-coupled bile acid receptor 1 (GPBAR1)] on cancer progression is dependent on the tissue where it is activated. In this report, the function of TGR5 expression in cancer was studied using a bioinformatic approach. TGR5 expression in ampullary adenocarcinoma and normal duodenum was compared by western blotting, reverse transcription polymerase chain reaction, and immunohistochemistry (IHC)...
October 2016: Oncology Reports
https://www.readbyqxmd.com/read/27503935/preserved-gut-microbial-diversity-accompanies-upregulation-of-tgr5-and-hepatobiliary-transporters-in-bile-acid-treated-animals-receiving-parenteral-nutrition
#17
Ajay Kumar Jain, Abhineet Sharma, Sumit Arora, Keith Blomenkamp, Ik Chan Jun, Robert Luong, David John Westrich, Aayush Mittal, Paula M Buchanan, Miguel A Guzman, John Long, Brent A Neuschwander-Tetri, Jeffery Teckman
BACKGROUND: Parenteral nutrition (PN) is a lifesaving therapy but is associated with gut atrophy and cholestasis. While bile acids (BAs) can modulate intestinal growth via gut receptors, the gut microbiome likely influences gut proliferation and inflammation. BAs also regulate the bile salt export pump (BSEP) involved in cholestasis. We hypothesized that the BA receptor agonist oleanolic acid (OA) regulates gut TGR5 receptor and modulates gut microbiota to prevent PN-associated injury...
August 8, 2016: JPEN. Journal of Parenteral and Enteral Nutrition
https://www.readbyqxmd.com/read/27475255/bile-acid-receptor-agonists-int747-and-int777-decrease-oestrogen-deficiency-related-postmenopausal-obesity-and-hepatic-steatosis-in-mice
#18
Monique C de Oliveira, Eduardo H Gilglioni, Bouke A de Boer, Jurgen H Runge, Dirk R de Waart, Clairce L Salgueiro, Emy L Ishii-Iwamoto, Ronald P J Oude Elferink, Ingrid C Gaemers
: Menopause is often followed by obesity and, related to this, non-alcoholic fatty liver disease (NAFLD). Two bile acid (BA) receptors, farnesoid X receptor (FXR) and G-protein-coupled receptor TGR5, have emerged as putative therapeutic targets for obesity and NAFLD. AIM OF THIS STUDY: to evaluate the efficacy of selective agonists INT747/obeticholic acid (FXR) and INT777 (TGR5) as novel treatments for the metabolic effects of oestrogen deficiency. Ovariectomized (OVX) or sham-operated (SHAM) mice were fed a high-fat diet (HFD) for 5weeks...
November 2016: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/27470217/tgr5-suppresses-high-glucose-induced-upregulation-of-fibronectin-and-transforming-growth-factor-%C3%AE-1-in-rat-glomerular-mesangial-cells-by-inhibiting-rhoa-rock-signaling
#19
Fengxiao Xiong, Xuejuan Li, Zhiying Yang, Yu Wang, Wenyan Gong, Junying Huang, Cheng Chen, Peiqing Liu, Heqing Huang
RhoA/ROCK can cause renal inflammation and fibrosis in the context of diabetes by activating nuclear factor-κB (NF-κB). TGR5 is known for its role in maintaining metabolic homeostasis and anti-inflammation, which is closely related to NF-κB inhibition. Given that TGR5 is highly enriched in kidney, we aim to investigate the regulatory role of TGR5 on fibronectin (FN) and transforming growth factor-β1 (TGF-β1) in high glucose (HG)-treated rat glomerular mesangial cells (GMCs). Both the factors are closely related to renal inflammations and mediated by NF-κB...
July 28, 2016: Endocrine
https://www.readbyqxmd.com/read/27459945/the-roles-of-bile-acids-and-sphingosine-1-phosphate-signaling-in-the-hepatobiliary-diseases
#20
REVIEW
Masayuki Nagahashi, Kizuki Yuza, Yuki Hirose, Masato Nakajima, Rajesh Ramanathan, Nitai C Hait, Phillip B Hylemon, Huiping Zhou, Kazuaki Takabe, Toshifumi Wakai
Based on research carried out over the last decade, it has become increasingly evident that bile acids act not only as detergents, but also as important signaling molecules that exert various biological effects via activation of specific nuclear receptors and cell signaling pathways. Bile acids also regulate the expression of numerous genes encoding enzymes and proteins involved in the synthesis and metabolism of bile acids, glucose, fatty acids, and lipoproteins, as well as energy metabolism. Receptors activated by bile acids include, farnesoid X receptor α, pregnane X receptor, vitamin D receptor, and G protein-coupled receptors, TGR5, muscarinic receptor 2, and sphingosine-1-phosphate receptor (S1PR)2...
September 2016: Journal of Lipid Research
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