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FXR FGF15

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https://www.readbyqxmd.com/read/29486523/intestine-farnesoid-x-receptor-agonist-and-the-gut-microbiota-activate-g-protein-bile-acid-receptor-1-signaling-to-improve-metabolism
#1
Preeti Pathak, Xie Cen, Robert G Nichols, Jessica M Ferrell, Shannon Boehme, Kristopher W Krausz, Andrew D Patterson, Frank J Gonzalez, John Y L Chiang
Bile acids activate farnesoid X receptor (FXR) and G protein-coupled bile acid receptor-1 (Gpbar-1, aka TGR5) to regulate bile acid metabolism and glucose and insulin sensitivity. FXR and TGR5 are co-expressed in the enteroendocrine L cells but their roles in integrated regulation of metabolism are not completely understood. We reported recently that activation of FXR induces TGR5 to stimulate glucagon-like peptide-1 (GLP-1) secretion to improve insulin sensitivity and hepatic metabolism. In this study, we used the intestine-restricted FXR agonist fexaramine (FEX) to study the effect of activation of intestinal FXR on the gut microbiome, bile acid metabolism, and FXR and TGR5 signaling...
February 27, 2018: Hepatology: Official Journal of the American Association for the Study of Liver Diseases
https://www.readbyqxmd.com/read/29382564/diabetic-cognitive-dysfunction-is-associated-with-increased-bile-acids-in-liver-and-activation-of-bile-acid-signaling-in-intestine
#2
Xue Wang, Fangyu Wang, Yidan Zhang, Hui Xiong, Yanjun Zhang, Pengwei Zhuang, Youcai Zhang
Impaired regulation of bile acid (BA) homeostasis has been suggested to be associated with adverse metabolic consequences. However, whether BA homeostasis is altered in diabetes-induced cognitive dysfunction (DCD) remains unknown. In the present study, mice were divided into four groups, namely normal control (NC) group, high-fat diet (HFD) group, diabetes without cognitive dysfunction (unDCD) group, and DCD group. Compared to HFD mice, the concentration of total BAs in liver was higher in unDCD and DCD mice, due to increased intestinal BA absorption...
May 1, 2018: Toxicology Letters
https://www.readbyqxmd.com/read/29381405/the-influences-of-cholecystectomy-on-the-circadian-rhythms-of-bile-acids-as-well-as-the-enterohepatic-transporters-and-enzymes-systems-in-mice
#3
Fan Zhang, Yingting Duan, Lili Xi, Mengmeng Wei, Axi Shi, Yan Zhou, Yuhui Wei, Xinan Wu
Bile acids (BAs), the most important endogenous and signaling molecules regulate the target transporters and enzymes at transcriptional level, participate in a wide variety of processes throughout the entire gastrointestinal tract to orchestrate homeostasis in vivo. BAs and their metabolism and transportation appear to follow the clear circadian rhythms, and they are recently proposed also as the potential chronobiological signals that can affect the molecular clock mechanism. Cholecystectomy are believed to affect the circadian rhythms of BAs and the relevant enterohepatic transporters and enzymes systems and their regulatory signaling pathways, for the reason that the circadian cycle of gallbladder filling and emptying play a pivotal role in controlling the flow of bile into the intestine and the enterohepatic circulation of BAs...
January 30, 2018: Chronobiology International
https://www.readbyqxmd.com/read/29290621/a-gut-brain-axis-regulating-glucose-metabolism-mediated-by-bile-acids-and-competitive-fibroblast-growth-factor-actions-at-the-hypothalamus
#4
Shunmei Liu, Genevieve Marcelin, Clemence Blouet, Jae Hoon Jeong, Young-Hwan Jo, Gary J Schwartz, Streamson Chua
OBJECTIVE: Bile acids have been implicated as important regulators of glucose metabolism via activation of FXR and GPBAR1. We have previously shown that FGF19 can modulate glucose handling by suppressing the activity of hypothalamic AGRP/NPY neurons. As bile acids stimulate the release of FGF19/FGF15 into the circulation, we pursued the potential of bile acids to improve glucose tolerance via a gut-brain axis involving FXR and FGF15/FGF19 within enterocytes and FGF receptors on hypothalamic AGRP/NPY neurons...
February 2018: Molecular Metabolism
https://www.readbyqxmd.com/read/29198707/impaired-vagus-function-in-rats-suppresses-bile-acid-synthesis-in-the-liver-by-disrupting-tight-junctions-and-activating-fxr-fgf15-signaling-in-the-intestine
#5
Fangyu Wang, Zhiqiang Lu, Xue Wang, Youcai Zhang
Bile acids (BAs) circulate between the liver and intestine, and regulate the homeostasis of glucose, lipid, and energy. Recent studies demonstrated an essential role of BAs in neurological diseases, suggesting an interaction between BAs and the nervous system. In the present study, we showed that impaired vagus function in rats induced by vagotomy resulted in an increase in bile flow without causing liver injury. The concentrations of unconjugated and glycine-conjugated BAs were increased in both serum and bile of rats after vagotomy, which was due to impaired tight junctions and thus increased passive absorption of BAs in the intestine...
January 1, 2018: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/29159825/modulation-of-the-intestinal-bile-acid-fxr-fgf15-axis-improves-alcoholic-liver-disease-in-mice
#6
Phillipp Hartmann, Katrin Hochrath, Angela Horvath, Peng Chen, Caroline T Seebauer, Cristina Llorente, Lirui Wang, Yazen Alnouti, Derrick E Fouts, Peter Stärkel, Rohit Loomba, Sally Coulter, Christopher Liddle, Ruth T Yu, Lei Ling, Stephen J Rossi, Alex M DePaoli, Michael Downes, Ronald M Evans, David A Brenner, Bernd Schnabl
Alcoholic liver disease is associated with changes in the intestinal microbiota. Functional consequences of alcohol-associated dysbiosis are largely unknown. The aim of this study was to identify a mechanism of how changes in the intestinal microbiota contribute to alcoholic liver disease. Metagenomic sequencing of intestinal contents demonstrated that chronic ethanol feeding in mice is associated with an overrepresentation of bacterial genomic DNA encoding choloylglycine hydrolase, which deconjugates bile acids in the intestine...
November 21, 2017: Hepatology: Official Journal of the American Association for the Study of Liver Diseases
https://www.readbyqxmd.com/read/28973556/editor-s-highlight-clofibrate-decreases-bile-acids-in-livers-of-male-mice-by-increasing-biliary-bile-acid-excretion-in-a-ppar%C3%AE-dependent-manner
#7
Youcai Zhang, Andrew J Lickteig, Iván L Csanaky, Curtis D Klaassen
Fibrates and their receptor, namely peroxisome proliferator-activated receptor α (PPARα), have been reported to regulate bile acid (BA) synthesis and transport. However, the effect of fibrate treatment and PPARα activation on BA homeostasis remains controversial. In this study, both wild-type (WT) and PPARα-null male mice were treated with clofibrate (CLOF) for 4 days to evaluate the effects of short-term PPARα activation on BA homeostasis. Although a decrease in total BAs (ΣBAs) was observed in livers of CLOF-treated WT mice, it was not observed in PPARα-null mice...
December 1, 2017: Toxicological Sciences: An Official Journal of the Society of Toxicology
https://www.readbyqxmd.com/read/28969019/repression-of-intestinal-transporters-and-fxr-fgf15-signaling-explains-bile-acids-dysregulation-in-experimental-colitis-associated-colon-cancer
#8
Lijuan Cao, Yuan Che, Tuo Meng, Shanshan Deng, Jun Zhang, Min Zhao, Wanfeng Xu, Dandan Wang, Zhichen Pu, Guangji Wang, Haiping Hao
Bile acids (BAs) are important endogenous signaling molecules that play vital roles in the pathological development of various diseases including colitis-associated cancer (CAC). BAs were previously found dysregulated under conditions of CAC; however, the exact patterns and underlying molecular mechanisms remain largely elusive. Based on the development of a method for comprehensive analysis of BAs, this study aims to elucidate the dysregulation patterns and involved mechanisms in a typical CAC model induced by azoxymethane (AOM)/dextran sodium sulfate (DSS)...
September 8, 2017: Oncotarget
https://www.readbyqxmd.com/read/28946907/the-relationship-between-bile-acid-concentration-glucagon-like-peptide-1-fibroblast-growth-factor-15-and-bile-acid-receptors-in-rats-during-progression-of-glucose-intolerance
#9
Xinfeng Yan, Peicheng Li, Zhaosheng Tang, Bo Feng
BACKGROUND: Recent studies show that bile acids are involved in glucose and energy homeostasis through activation of G protein coupled membrane receptor (TGR5) and farnesoid X receptor (FXR). A few researches have explored changes of TGR5 and FXR in animals with impaired glucose regulation. This study aimed to observe changes of plasma total bile acids (TBA), glucagon-like-peptide 1 (GLP-1), fibroblast growth factor 15 (FGF15), intestinal expressions of TGR5 and FXR, and correlations between them in rats with glucose intolerance...
September 25, 2017: BMC Endocrine Disorders
https://www.readbyqxmd.com/read/28843503/cyp7a1-is-continuously-increased-with-disrupted-fxr-mediated-feedback-inhibition-in-hypercholesterolemic-tallyho-jng-mice
#10
Eun-Ah Lee, Dong-In Lee, Hee-Yoen Kim, Sung-Hoon Ahn, Hye-Rim Seong, Won Hoon Jung, Ki Young Kim, Sungsub Kim, Sang Dal Rhee
TALLYHO/Jng (TH) mice reveal hypercholesterolemia at an early age before their plasma glucose levels have increased. The increased plasma cholesterol should be related to bile acids (BAs) metabolism, because cholesterol is the precursor of BAs and BAs change cholesterol metabolism in a feedback manner. We analyzed the BAs pool size, BAs composition, and expression levels of several proteins that have key roles in BAs synthesis, excretion, and reabsorption and compared them to those of C57BL/6 (B6) mice to study BAs metabolism in TH mice...
January 2018: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/28711947/repression-of-intestinal-transporters-and-fxr-fgf15-signaling-explains-bile-acids-dysregulation-in-experimental-colitis-associated-colon-cancer
#11
Lijuan Cao, Yuan Che, Tuo Meng, Shanshan Deng, Jun Zhang, Min Zhao, Wanfeng Xu, Dandan Wang, Zhichen Pu, Guangji Wang, Haiping Hao
Bile acids (BAs) are important endogenous signaling molecules that play vital roles in the pathological development of various diseases including colitis-associated cancer (CAC). BAs were previously found dysregulated under conditions of CAC; however, the exact patterns and underlying molecular mechanisms remain largely elusive. Based on the development of a method for comprehensive analysis of BAs, this study aims to elucidate the dysregulation patterns and involved mechanisms in a typical CAC model induced by azoxymethane (AOM)/dextran sodium sulfate (DSS)...
June 28, 2017: Oncotarget
https://www.readbyqxmd.com/read/28709961/bile-acids-fgf15-19-and-liver-regeneration-from-mechanisms-to-clinical-applications
#12
REVIEW
Gloria Alvarez-Sola, Iker Uriarte, Maria U Latasa, Maddalen Jimenez, Marina Barcena-Varela, Eva Santamaría, Raquel Urtasun, Carlos Rodriguez-Ortigosa, Jesús Prieto, Pedro Berraondo, Maite G Fernandez-Barrena, Carmen Berasain, Matías A Avila
The liver has an extraordinary regenerative capacity rapidly triggered upon injury or resection. This response is intrinsically adjusted in its initiation and termination, a property termed the "hepatostat". Several molecules have been involved in liver regeneration, and among them bile acids may play a central role. Intrahepatic levels of bile acids rapidly increase after resection. Through the activation of farnesoid X receptor (FXR), bile acids regulate their hepatic metabolism and also promote hepatocellular proliferation...
April 2018: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/28580281/glucagon-like-peptide-2-promotes-gallbladder-refilling-via-a-tgr5-independent-glp-2r-dependent-pathway
#13
Bernardo Yusta, Dianne Matthews, Grace B Flock, John R Ussher, Brigitte Lavoie, Gary M Mawe, Daniel J Drucker
OBJECTIVE: Glucagon-like peptides (GLPs) are secreted from enteroendocrine cells in response to nutrients and bile acids and control metabolism via actions on structurally-related yet distinct G protein coupled receptors. GLP-1 regulates gut motility, appetite, islet function, and glucose homeostasis, whereas GLP-2 enhances intestinal nutrient absorption. GLP-1R agonists are used to treat diabetes and obesity, and a GLP-2R agonist is approved to treat short bowel syndrome. Unexpectedly, reports of gallbladder disease have been associated with the use of both GLP-1R and GLP-2R agonists and after bariatric surgery, although the mechanisms remain unknown...
June 2017: Molecular Metabolism
https://www.readbyqxmd.com/read/28474246/pectin-penta-oligogalacturonide-suppresses-intestinal-bile-acids-absorption-and-downregulates-the-fxr-fgf15-axis-in-high-cholesterol-fed-mice
#14
Rugang Zhu, Yuting Hou, Yandi Sun, Tuoping Li, Jungang Fan, Gang Chen, Junxiu Wei
Haw pectin penta-oligogalacturonide (HPPS), purified from the hydrolysates of haw pectin, has important role in decreasing hepatic cholesterol accumulation and promoting bile acids (BA) excretion in the feces of mice fed a high-cholesterol diet (HCD). However, the mechanism is not clear. This study aims to investigate the effects of HPPS on BA reabsorption in ileum and biosynthesis in liver of mice. Results showed that HPPS increased fecal BA output by approximately 110%, but decreased ileal BA and the total BA pool size by approximately 47 and 36%, respectively, compared to HCD...
June 2017: Lipids
https://www.readbyqxmd.com/read/28446510/a-postprandial-fgf19-shp-lsd1-regulatory-axis-mediates-epigenetic-repression-of-hepatic-autophagy
#15
Sangwon Byun, Young-Chae Kim, Yang Zhang, Bo Kong, Grace Guo, Junichi Sadoshima, Jian Ma, Byron Kemper, Jongsook Kim Kemper
Lysosome-mediated autophagy is essential for cellular survival and homeostasis upon nutrient deprivation, but is repressed after feeding. Despite the emerging importance of transcriptional regulation of autophagy by nutrient-sensing factors, the role for epigenetic control is largely unexplored. Here, we show that Small Heterodimer Partner (SHP) mediates postprandial epigenetic repression of hepatic autophagy by recruiting histone demethylase LSD1 in response to a late fed-state hormone, FGF19 (hFGF19, mFGF15)...
June 14, 2017: EMBO Journal
https://www.readbyqxmd.com/read/28202906/bar502-a-dual-fxr-and-gpbar1-agonist-promotes-browning-of-white-adipose-tissue-and-reverses-liver-steatosis-and-fibrosis
#16
Adriana Carino, Sabrina Cipriani, Silvia Marchianò, Michele Biagioli, Chiara Santorelli, Annibale Donini, Angela Zampella, Maria Chiara Monti, Stefano Fiorucci
Non-alcoholic steatohepatitis (NASH) is a highly prevalent chronic liver disease. Here, we have investigated whether BAR502, a non-bile acid, steroidal dual ligand for FXR and GPBAR1, reverses steato-hepatitis in mice fed a high fat diet (HFD) and fructose. After 9 week, mice on HFD gained ≈30% of b.w (P < 0.01 versus naïve) and were insulin resistant. These overweighting and insulin resistant mice were randomized to receive HFD or HFD in combination with BAR502. After 18 weeks, HFD mice developed NASH like features with severe steato-hepatitis and fibrosis, increased hepatic content of triacylglycerol and cholesterol and expression of SREPB1c, FAS, ApoC2, PPARα and γ, α-SMA, α1 collagen and MCP1 mRNAs...
February 16, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28065787/intestinal-farnesoid-x-receptor-controls-transintestinal-cholesterol-excretion-in-mice
#17
Jan Freark de Boer, Marleen Schonewille, Marije Boesjes, Henk Wolters, Vincent W Bloks, Trijnie Bos, Theo H van Dijk, Angelika Jurdzinski, Renze Boverhof, Justina C Wolters, Jan A Kuivenhoven, Jan M van Deursen, Ronald P J Oude Elferink, Antonio Moschetta, Claus Kremoser, Henkjan J Verkade, Folkert Kuipers, Albert K Groen
BACKGROUND & AIMS: The role of the intestine in the maintenance of cholesterol homeostasis increasingly is recognized. Fecal excretion of cholesterol is the last step in the atheroprotective reverse cholesterol transport pathway, to which biliary and transintestinal cholesterol excretion (TICE) contribute. The mechanisms controlling the flux of cholesterol through the TICE pathway, however, are poorly understood. We aimed to identify mechanisms that regulate and stimulate TICE. METHODS: We performed studies with C57Bl/6J mice, as well as with mice with intestine-specific knockout of the farnesoid X receptor (FXR), mice that express an FXR transgene specifically in the intestine, and ABCG8-knockout mice...
April 2017: Gastroenterology
https://www.readbyqxmd.com/read/28043194/differential-regulation-of-intestinal-efflux-transporters-by-pregnancy-in-mice
#18
Jamie E Moscovitz, Gabriel Yarmush, Guadalupe Herrera-Garcia, Grace L Guo, Lauren M Aleksunes
1. In the intestines, the nuclear receptors farnesoid X receptor (Fxr) and pregnane X receptor (Pxr) regulate the transcription of metabolizing enzymes and transporters that dictate the absorption of nutrients and xenobiotics. 2. Here, we sought to determine whether Fxr and Pxr signaling pathways are disrupted in response to high-circulating concentrations of steroid hormones late in pregnancy leading to altered transporter expression. To test this, ileum were collected from virgin and pregnant C57BL/6 mice on gestation days 14, 17 and 19...
November 2017: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/27956475/induction-of-farnesoid-x-receptor-signaling-in-germ-free-mice-colonized-with-a-human-microbiota
#19
Annika Wahlström, Petia Kovatcheva-Datchary, Marcus Ståhlman, Muhammad-Tanweer Khan, Fredrik Bäckhed, Hanns-Ulrich Marschall
The gut microbiota influences the development and progression of metabolic diseases partly by metabolism of bile acids (BAs) and modified signaling through the farnesoid X receptor (FXR). In this study, we aimed to determine how the human gut microbiota metabolizes murine BAs and affects FXR signaling in colonized mice. We colonized germ-free mice with cecal content from a mouse donor or feces from a human donor and euthanized the mice after short-term (2 weeks) or long-term (15 weeks) colonization. We analyzed the gut microbiota and BA composition and expression of FXR target genes in ileum and liver...
February 2017: Journal of Lipid Research
https://www.readbyqxmd.com/read/27895309/hepatocyte-specific-expression-of-an-oncogenic-variant-of-%C3%AE-catenin-results-in-cholestatic-liver-disease
#20
Ursula J Lemberger, Claudia D Fuchs, Matthias Karer, Stefanie Haas, Tatjana Stojakovic, Christian Schöfer, Hanns-Ulrich Marschall, Fritz Wrba, Makoto M Taketo, Gerda Egger, Michael Trauner, Christoph H Österreicher
BACKGROUND: The Wnt/β-catenin signaling pathway plays a crucial role in embryonic development, tissue homeostasis, wound healing and malignant transformation in different organs including the liver. The consequences of continuous β-catenin signaling in hepatocytes remain elusive. RESULTS: Livers of Ctnnb1CA hep mice were characterized by disturbed liver architecture, proliferating cholangiocytes and biliary type of fibrosis. Serum ALT and bile acid levels were significantly increased in Ctnnb1CA hep mice...
December 27, 2016: Oncotarget
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