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FXR FGF15

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https://www.readbyqxmd.com/read/28973556/clofibrate-decreases-bile-acids-in-livers-of-male-mice-by-increasing-biliary-bile-acid-excretion-in-a-ppar%C3%AE-dependent-manner
#1
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 the present 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 bile acid (BA) homeostasis. While a decrease in total BAs was observed in livers of CLOF-treated WT mice, it was not observed in PPARα-null mice...
September 13, 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
#2
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
#3
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
#4
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...
August 24, 2017: 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
#5
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
#6
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...
July 11, 2017: 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
#7
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
#8
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%C3%A2-mediates-epigenetic-repression-of-hepatic%C3%A2-autophagy
#9
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
#10
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
#11
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
#12
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
#13
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
#14
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
https://www.readbyqxmd.com/read/27789682/disrupted-murine-gut-to-human-liver-signaling-alters-bile-acid-homeostasis-in-humanized-mouse-liver-models
#15
Edwin C Y Chow, Holly P Quach, Yueping Zhang, Jason Z Y Wang, David C Evans, Albert P Li, Jose Silva, Rommel G Tirona, Yurong Lai, K Sandy Pang
The humanized liver mouse model is being exploited increasingly for human drug metabolism studies. However, its model stability, intercommunication between human hepatocytes and mouse nonparenchymal cells in liver and murine intestine, and changes in extrahepatic transporter and enzyme expressions have not been investigated. We examined these issues in FRGN [fumarylacetoacetate hydrolase (Fah-/-), recombination activating gene 2 (Rag2-/-), and interleukin 2 receptor subunit gamma (IL-2rg -/-) triple knockout] on nonobese diabetic (NOD) background] and chimeric mice: mFRGN and hFRGN (repopulated with mouse or human hepatocytes, respectively)...
January 2017: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/27639250/sirtuin-1-activation-alleviates-cholestatic-liver-injury-in-a-cholic-acid-fed-mouse-model-of-cholestasis
#16
Supriya R Kulkarni, Carol J Soroka, Lee R Hagey, James L Boyer
Sirtuin1 (Sirt1; mammalian homolog of Saccharomyces cerevisiae enzyme Sir2) is a transcriptional and transactivational regulator of murine farnesoid X receptor (Fxr), which is the primary bile acid (BA) sensor, and critical regulator of BA metabolism in physiological and pathophysiological conditions. Previous studies have suggested compromised Sirt1 expression in rodent models of cholestatic liver injury. We hypothesized that Sirt1 could be potentially targeted to alleviate cholestatic liver injury. In cultured primary human hepatocytes, SIRT1 messenger RNA was down-regulated after GCA treatment, potentially through induction of microRNA (miR)-34a, whereas tauroursodeoxycholic acid induced SIRT1 expression without affecting miR-34a expression...
December 2016: Hepatology: Official Journal of the American Association for the Study of Liver Diseases
https://www.readbyqxmd.com/read/27609522/restoration-of-enterohepatic-bile-acid-pathways-in-pregnant-mice-following-short-term-activation-of-fxr-by-gw4064
#17
Jamie E Moscovitz, Bo Kong, Kyle Buckley, Brian Buckley, Grace L Guo, Lauren M Aleksunes
The farnesoid X receptor (Fxr) controls bile acid homeostasis by coordinately regulating the expression of synthesizing enzymes (Cyp7a1, Cyp8b1), conjugating enzymes (Bal, Baat) and transporters in the ileum (Asbt, Ostα/β) and liver (Ntcp, Bsep, Ostβ). Transcriptional regulation by Fxr can be direct, or through the ileal Fgf15/FGF19 and hepatic Shp pathways. Circulating bile acids are increased during pregnancy due to hormone-mediated disruption of Fxr signaling. While this adaptation enhances lipid absorption, elevated bile acids may predispose women to develop maternal cholestasis...
November 1, 2016: Toxicology and Applied Pharmacology
https://www.readbyqxmd.com/read/27580383/alterations-in-enterohepatic-fgf15-signaling-and-changes-in-bile-acid-composition-depend-on-localization-of-murine-intestinal-inflammation
#18
Monika Rau, Bruno Stieger, Maria J Monte, Johannes Schmitt, Daniel Jahn, Isabelle Frey-Wagner, Tina Raselli, Jose J G Marin, Beat Müllhaupt, Gerhard Rogler, Andreas Geier
BACKGROUND: Fibroblast growth factor (FGF) 15/19 is part of the gut-liver crosstalk accounting for bile acid (BA) metabolism regulation. Dysregulation of fibroblast growth factor 15/19 signaling is observed in different pathological conditions, for example, in gastrointestinal diseases such as inflammatory bowel disease (IBD). To understand the molecular bases, we analyzed the enterohepatic regulation of Fgf15-mediated pathway in 2 different inflammatory bowel disease mouse models. METHODS: Target genes of the BA-farnesoid-X-receptor (Fxr)-Ffg15 axis were quantified by RT-PCR or western blotting in gut and liver of dextran sulfate sodium (DSS)-treated and IL10 mice...
October 2016: Inflammatory Bowel Diseases
https://www.readbyqxmd.com/read/27048804/resveratrol-attenuates-trimethylamine-n-oxide-tmao-induced-atherosclerosis-by-regulating-tmao-synthesis-and-bile-acid-metabolism-via-remodeling-of-the-gut-microbiota
#19
Ming-liang Chen, Long Yi, Yong Zhang, Xi Zhou, Li Ran, Jining Yang, Jun-dong Zhu, Qian-yong Zhang, Man-tian Mi
UNLABELLED: The gut microbiota is found to be strongly associated with atherosclerosis (AS). Resveratrol (RSV) is a natural phytoalexin with anti-AS effects; however, its mechanisms of action remain unclear. Therefore, we sought to determine whether the anti-AS effects of RSV were related to changes in the gut microbiota. We found that RSV attenuated trimethylamine-N-oxide (TMAO)-induced AS in ApoE(-/-) mice. Meanwhile, RSV decreased TMAO levels by inhibiting commensal microbial trimethylamine (TMA) production via gut microbiota remodeling in mice...
April 5, 2016: MBio
https://www.readbyqxmd.com/read/27018382/protective-effects-of-lactobacillus-rhamnosus-gg-against-dyslipidemia-in-high-fat-diet-induced-obese-mice
#20
Bobae Kim, Kun-Young Park, Yosep Ji, Soyoung Park, Wilhelm Holzapfel, Chang-Kee Hyun
Recent reports suggest that gut microbiota can be a major determinant of dyslipidemia and non-alcoholic fatty liver disease (NAFLD) and its modulation by treating probiotics is a valid strategy to exert a protective effect. In this study, high-fat diet (HFD)-fed mice were orally administrated with Lactobacillus rhamnosus GG (LGG) for 13 weeks. Significant reductions in the weights of the liver, mesenteric and subcutaneous adipose tissues were observed in LGG-treated HFD-fed mice compared to LGG-non-treated controls...
April 29, 2016: Biochemical and Biophysical Research Communications
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