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Farnesoid x receptor

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https://www.readbyqxmd.com/read/29761207/omics-based-responses-induced-by-bosentan-in-human-hepatoma-heparg-cell-cultures
#1
Robim M Rodrigues, Laxmikanth Kollipara, Umesh Chaudhari, Agapios Sachinidis, René P Zahedi, Albert Sickmann, Annette Kopp-Schneider, Xiaoqi Jiang, Hector Keun, Jan Hengstler, Marlies Oorts, Pieter Annaert, Eef Hoeben, Eva Gijbels, Joery De Kock, Tamara Vanhaecke, Vera Rogiers, Mathieu Vinken
Bosentan is well known to induce cholestatic liver toxicity in humans. The present study was set up to characterize the hepatotoxic effects of this drug at the transcriptomic, proteomic, and metabolomic levels. For this purpose, human hepatoma-derived HepaRG cells were exposed to a number of concentrations of bosentan during different periods of time. Bosentan was found to functionally and transcriptionally suppress the bile salt export pump as well as to alter bile acid levels. Pathway analysis of both transcriptomics and proteomics data identified cholestasis as a major toxicological event...
May 14, 2018: Archives of Toxicology
https://www.readbyqxmd.com/read/29761098/discovery-of-natural-products-as-novel-and-potent-fxr-antagonists-by-virtual-screening
#2
Yanyan Diao, Jing Jiang, Shoude Zhang, Shiliang Li, Lei Shan, Jin Huang, Weidong Zhang, Honglin Li
Farnesoid X receptor (FXR) is a member of nuclear receptor family involved in multiple physiological processes through regulating specific target genes. The critical role of FXR as a transcriptional regulator makes it a promising target for diverse diseases, especially those related to metabolic disorders such as diabetes and cholestasis. However, the underlying activation mechanism of FXR is still a blur owing to the absence of proper FXR modulators. To identify potential FXR modulators, an in-house natural product database (NPD) containing over 4,000 compounds was screened by structure-based virtual screening strategy and subsequent hit-based similarity searching method...
2018: Frontiers in Chemistry
https://www.readbyqxmd.com/read/29759109/hypocholesterolaemic-effect-of-whole-grain-highland-hull-less-barley-in-rats-fed-a-high-fat-diet
#3
Xuejuan Xia, Guannan Li, Jiaxin Song, Jiong Zheng, Jianquan Kan
Whole-grain highland hull-less barley (WHLB) contains high amounts of bioactive compounds that potentially exhibit cholesterol-lowering effects. This study investigated the hypocholesterolaemic effect of WHLB. A total of seventy-two male Sprague-Dawley rats were divided into four groups and were fed with the normal control diet, high-fat diet (HFD) and HFD containing low or high dose (10 or 48·95 %) of WHLB. High dose of WHLB significantly decreased the organ indexes of liver and abdominal fat and lipid levels of plasma and liver in HFD rats...
May 2018: British Journal of Nutrition
https://www.readbyqxmd.com/read/29758112/novel-and-emerging-therapies-for-cholestatic-liver-diseases
#4
Jordan Goldstein, Cynthia Levy
While bile acids are important for both digestion and signaling, hydrophobic bile acids can be harmful especially when in high concentrations. Mechanisms for protection of cholangiocytes against bile acid cytotoxicity include negative feedback loops via farnesoid X nuclear receptor (FXR) activation, the bicarbonate umbrella, cholehepatic shunting and anti-inflammatory signaling, among others. By altering or overwhelming these defense mechanisms, cholestatic diseases such as primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) can further progress to biliary cirrhosis, end-stage liver disease and death or liver transplantation...
May 14, 2018: Liver International: Official Journal of the International Association for the Study of the Liver
https://www.readbyqxmd.com/read/29743187/the-effects-of-farnesoid-x-receptor-activation-on-arachidonic-acid-metabolism-nf-kb-signaling-and-hepatic-inflammation
#5
Zhibo Gai, Michele Visentin, Ting Gui, Lin Zhao, Wolfgang E Thasler, Stephanie Hausler, Ivan Hartling, Alessio Cremonesi, Christian Hiller, Gerd A Kullak-Ublick
Inflammation has a recognized role in non-alcoholic fatty liver disease (NAFLD) progression. The present work studied the effect of high fat diet (HFD) on arachidonic acid metabolism in the liver and investigated the role of the farnesoid X receptor (FXR, NR1H4) in eicosanoid biosynthetic pathways and NF-kB signaling, major modulators of the inflammatory cascade. Mice were fed a HFD to induce NAFLD, then, treated with the FXR ligand obeticholic acid (OCA). Histology and gene expression analysis were performed on liver tissue...
May 9, 2018: Molecular Pharmacology
https://www.readbyqxmd.com/read/29739889/farnesoid-x-receptor-is-essential-for-the-survival-of-renal-medullary-collecting-duct-cells-under-hypertonic-stress
#6
Sujuan Xu, Shizheng Huang, Zhilin Luan, Tingyue Chen, Yuanyi Wei, Miaomiao Xing, Yaqing Li, Chunxiu Du, Bing Wang, Feng Zheng, Nanping Wang, Youfei Guan, Jan-Åke Gustafsson, Xiaoyan Zhang
Hypertonicity in renal medulla is critical for the kidney to produce concentrated urine. Renal medullary cells have to survive high medullary osmolarity during antidiuresis. Previous study reported that farnesoid X receptor (FXR), a nuclear receptor transcription factor activated by endogenous bile acids, increases urine concentrating ability by up-regulating aquaporin 2 expression in medullary collecting duct cells (MCDs). However, whether FXR is also involved in the maintenance of cell survival of MCDs under dehydration condition and hypertonic stress remains largely unknown...
May 8, 2018: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/29733835/mechanisms-of-mafg-dysregulation-in-cholestatic-liver-injury-and-development-of-liver-cancer
#7
Ting Liu, Heping Yang, Wei Fan, Jian Tu, Tony W H Li, Jiaohong Wang, Hong Shen, JinWon Yang, Ting Xiong, Justin Steggerda, Zhenqiu Liu, Mazen Noureddin, Stephanie S Maldonado, Alagappan Annamalai, Ekihiro Seki, José M Mato, Shelly C Lu
BACKGROUND & AIMS: MAF bZIP transcription factor G (MAFG) is activated by the farnesoid X receptor (FXR) to repress bile acid synthesis. However, expression of MAFG increases during cholestatic liver injury in mice and in cholangiocarcinomas. MAFG interacts directly with methionine adenosyltransferase 1A (MAT1A) and other transcription factors at the E-box element to repress transcription. We studied mechanisms of MAFG upregulation in cholestatic tissues and the pathways by which S-adenosylmethionine (SAMe) and ursodeoxycholic acid (UDCA) prevent the increase in MAFG expression...
May 4, 2018: Gastroenterology
https://www.readbyqxmd.com/read/29721568/hepatoprotection-of-auraptene-from-peels-of-citrus-fruits-against-thioacetamide-induced-hepatic-fibrosis-in-mice-by-activating-farnesoid-x-receptor
#8
Xiaoguang Gao, Changyuan Wang, Chenqing Ning, Kexin Liu, Xinyuan Wang, Zhihao Liu, Huijun Sun, Xiaodong Ma, Pengyuan Sun, Qiang Meng
Hepatic fibrosis is a pathological process that eventually leads to the development of cirrhosis and liver cancer by various types of chronic liver disease. To date, there is no standard treatment for the progression of liver fibrosis. This study aims to investigate the hepatoprotection of auraptene (AUR), a simple coumarin contained in the peels of citrus fruits such as grapefruit, against thioacetamide (TAA)-induced hepatic fibrosis in mice. The involvement of farnesoid X receptor (FXR) in the anti-fibrotic effect of AUR was further elucidated using in vivo and in vitro experiments...
May 3, 2018: Food & Function
https://www.readbyqxmd.com/read/29720851/role-of-bile-acids-in-inflammatory-bowel-disease
#9
REVIEW
Elisa Tiratterra, Placido Franco, Emanuele Porru, Konstantinos H Katsanos, Dimitrios K Christodoulou, Giulia Roda
Bile acids (BAs) are the end product of cholesterol catabolism. Their synthesis is regulated by the nuclear receptor farnesoid X receptor, also involved in the control of their enterohepatic circulation. Inflammatory bowel diseases (IBD), which include Crohn's disease (CD) and ulcerative colitis (UC), are multifactorial diseases characterized by diarrhea. The pathogenesis of diarrhea in IBD is still debated. The most important factor is the inflammatory process of the intestinal wall, causing alterations of solute and water absorption/secretion, deterioration of epithelial cell integrity, disruption of the intestinal microflora homeostasis, and impairment of specific transport mechanisms within the gut (including that of BAs)...
May 2018: Annals of Gastroenterology: Quarterly Publication of the Hellenic Society of Gastroenterology
https://www.readbyqxmd.com/read/29718219/xenobiotic-nuclear-receptor-signaling-determines-molecular-pathogenesis-of-progressive-familial-intrahepatic-cholestasis
#10
Kang Ho Kim, Jong Min Choi, Feng Li, Armando Arizpe, Clavia Ruth Wooton-Kee, Sayeepriyadarshini Anakk, Sung Yun Jung, Milton J Finegold, David D Moore
Progressive familial intrahepatic cholestasis (PFIC) is a genetically heterogeneous disorder of bile flow disruption due to abnormal canalicular transport or impaired bile acid (BA) metabolism, causing excess BA accumulation and liver failure. We reported an intrahepatic cholestasis mouse model based on loss of function of both farnesoid X receptor (FXR; NR1H4) and small heterodimer partner (SHP, NR0B2) (DKO), which has strong similarities to human PFIC type 5. Here, we compare the pathogenesis of the DKO liver to that of another intrahepatic cholestasis model, Bsep-/-, which represents human PFIC2...
April 26, 2018: Endocrinology
https://www.readbyqxmd.com/read/29717168/allosteric-modulation-of-the-farnesoid-x-receptor-by-a-small-molecule
#11
Matthias Gabler, Jan Kramer, Jurema Schmidt, Julius Pollinger, Julia Weber, Astrid Kaiser, Frank Löhr, Ewgenij Proschak, Manfred Schubert-Zsilavecz, Daniel Merk
The bile acid activated transcription factor farnesoid X receptor (FXR) regulates numerous metabolic processes and is a rising target for the treatment of hepatic and metabolic disorders. FXR agonists have revealed efficacy in treating non-alcoholic steatohepatitis (NASH), diabetes and dyslipidemia. Here we characterize imatinib as first-in-class allosteric FXR modulator and report the development of an optimized descendant that markedly promotes agonist induced FXR activation in a reporter gene assay and FXR target gene expression in HepG2 cells...
May 1, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29701901/no-gut-no-gain-enteral-bile-acid-treatment-preserves-gut-growth-but-not-parenteral-nutrition-associated-liver-injury-in-a-novel-extensive-short-bowel-animal-model
#12
Gustavo Villalona, Amber Price, Keith Blomenkamp, Chandrashekhara Manithody, Saurabh Saxena, Thomas Ratchford, Matthew Westrich, Vindhya Kakarla, Shruthika Pochampally, William Phillips, Nicole Heafner, Niraja Korremla, Jose Greenspon, Miguel A Guzman, Ajay Kumar Jain
BACKGROUND: Parenteral nutrition (PN) provides nutrition intravenously; however, this life-saving therapy is associated with significant liver disease. Recent evidence indicates improvement in PN-associated injury in animals with intact gut treated with enteral bile acid (BA), chenodeoxycholic acid (CDCA), and a gut farnesoid X receptor (FXR) agonist, which drives the gut-liver cross talk (GLCT). We hypothesized that similar improvement could be translated in animals with short bowel syndrome (SBS)...
April 27, 2018: JPEN. Journal of Parenteral and Enteral Nutrition
https://www.readbyqxmd.com/read/29701277/review-article-therapeutic-bile-acids-and-the-risks-for-hepatotoxicity
#13
REVIEW
K Ashby, E E Navarro Almario, W Tong, J Borlak, R Mehta, M Chen
BACKGROUND: Bile acids play important roles in cholesterol metabolism and signal through farnesoid X receptor and G protein-coupled receptors. Given their importance in liver biology, bile acid therapy enables therapeutic applications beyond the treatment of cholestatic liver disease. However, predicting hepatotoxicity of bile acids in humans is obscured due to inconsistent extrapolations of animal data to humans. AIM: To review the evidence that could explain discordant bile acids hepatotoxicity observed in humans and animals...
April 27, 2018: Alimentary Pharmacology & Therapeutics
https://www.readbyqxmd.com/read/29697548/bile-acids-and-the-gut-microbiome-as-potential-targets-for-nafld-treatment
#14
Lixin Zhu, Robert D Baker, Ruixin Zhu, Susan S Baker
Semi-synthetic bile acid (BA) obeticholic acid (OCA), a potent farnesoid X receptor (FXR) agonist, exhibited beneficial effects on non-alcoholic fatty liver disease (NAFLD). However, OCA did not cause a resolution of non-alcoholic steatohepatitis (NASH). Here we discuss several prominent knowledge gaps in BA/FXR biology. Firstly, although many groups reported elevated serum BA levels, there are reports of decreased or normal serum BA levels in NAFLD, underlining the complexity of BA regulation by environmental and genetic factors...
April 23, 2018: Journal of Pediatric Gastroenterology and Nutrition
https://www.readbyqxmd.com/read/29689564/pulmonary-exposure-to-particulate-matter-pm2-5-affects-the-sensitivity-to-myocardial-ischemia-reperfusion-injury-through-farnesoid-x-receptor-induced-autophagy
#15
Fei Tong, Hua Zhang
BACKGROUND/AIMS: The purpose of this study was to investigate the effect of administering particulate matter (PM2.5) to the lungs on the sensitivity to myocardial ischemia/reperfusion injury (MI/RI) and the role of farnesoid-X-receptor (FXR)-induced autophagy in this process. METHODS: Male Sprague Dawley (SD) rats were subjected to 45 min of ischemia, and the lungs were exposed to 2.0 mg of PM2.5 in 0.3 mL of normal saline 5 min before reperfusion. After 24 h of reperfusion, the blood and myocardium were collected, and the myocardial infarct sizes, activities of serum creatine kinase (CK) and lactate dehydrogenase (LDH), and levels of serum high sensitivity C-reactive protein (hsCRP), interleukin-4 (IL-4), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), cardiac troponin T (cTnT), P-selectin and D-dimer were measured via biochemical analysis...
April 19, 2018: Cellular Physiology and Biochemistry
https://www.readbyqxmd.com/read/29677620/hippocampal-fxr-plays-a-role-in-the-pathogenesis-of-depression-a-preliminary-study-based-on-lentiviral-gene-modulation
#16
Wei-Guan Chen, Jia-Xuan Zheng, Xi Xu, Yu-Ming Hu, Yu-Min Ma
As a well-known bile acid receptor, the role of Farnesoid X receptor (FXR) in the digestive system and cardiovascular system has been widely explored. However, there are very few studies involving FXR in the central nervous system. In this study, we explored the role of FXR in the pathogenesis of depression, a serious and worldwide neuropsychiatric disease. It was found that chronic unpredictable mild stress (CUMS) fully enhanced the protein and mRNA expressions of FXR in hippocampus, but not medial prefrontal cortex (mPFC)...
April 10, 2018: Psychiatry Research
https://www.readbyqxmd.com/read/29675448/intestinal-farnesoid-x-receptor-activation-by-pharmacologic-inhibition-of-the-organic-solute-transporter-%C3%AE-%C3%AE
#17
Sandra M W van de Wiel, D Rudi de Waart, Ronald P J Oude Elferink, Stan F J van de Graaf
Background & Aims: The organic solute transporter α-β (OSTα-OSTβ) mainly facilitates transport of bile acids across the basolateral membrane of ileal enterocytes. Therefore, inhibition of OSTα-OSTβ might have similar beneficial metabolic effects as intestine-specific agonists of the major nuclear receptor for bile acids, the farnesoid X receptor (FXR). However, no OSTα-OSTβ inhibitors have yet been identified. Methods: Here, we developed a screen to identify specific inhibitors of OSTα-OSTβ using a genetically encoded Förster Resonance Energy Transfer (FRET)-bile acid sensor that enables rapid visualization of bile acid efflux in living cells...
March 2018: Cellular and Molecular Gastroenterology and Hepatology
https://www.readbyqxmd.com/read/29669937/bile-acids-regulate-cysteine-catabolism-and-glutathione-regeneration-to-modulate-hepatic-sensitivity-to-oxidative-injury
#18
Yifeng Wang, Jibiao Li, David Matye, Yuxia Zhang, Katie Dennis, Wen-Xing Ding, Tiangang Li
Bile acids are signaling molecules that critically control hepatocellular function. Disrupted bile acid homeostasis may be implicated in the pathogenesis of chronic liver diseases. Glutathione is an important antioxidant that protects the liver against oxidative injury. Various forms of liver disease share the common characteristics of reduced cellular glutathione and elevated oxidative stress. This study reports a potentially novel physiological function of bile acids in regulating hepatic sulfur amino acid and glutathione metabolism...
April 19, 2018: JCI Insight
https://www.readbyqxmd.com/read/29668847/adiponectin-determines-farnesoid-x-receptor-agonism-mediated-cardioprotection-against-post-infarction-remodeling-and-dysfunction
#19
Yunlong Xia, Fuyang Zhang, Shihao Zhao, Yueyang Li, Xiyao Chen, Erhe Gao, Xinyue Xu, Zhenyu Xiong, Xiaomeng Zhang, Jinglong Zhang, Huishou Zhao, Wei Wang, Helin Wang, Yanjie Guo, Yi Liu, Congye Li, Shan Wang, Ling Zhang, Wenjun Yan, Ling Tao
Aims: The farnesoid X receptor (FXR) is a member of the metabolic nuclear receptor superfamily that plays a critical regulatory role in cardiovascular physiology/pathology. However, the role of systemic FXR activation in the chronic phase in myocardial infarction (MI)-induced cardiac remodeling and dysfunction remains unclear. In this study, we aimed to elucidate the role of long-term FXR activation on post-MI cardiac remodeling and dysfunction. Methods and Results: Mice underwent either MI surgery or sham operation...
April 14, 2018: Cardiovascular Research
https://www.readbyqxmd.com/read/29660435/yangonin-protects-against-cholestasis-and-hepatotoxity-via-activation-of-farnesoid-x-receptor-in-vivo-and-in-vitro
#20
Xiaoguang Gao, Ting Fu, Changyuan Wang, Chenqing Ning, Kexin Liu, Zhihao Liu, Huijun Sun, Xiaodong Ma, Xiaokui Huo, Xiaobo Yang, Ming Zou, Qiang Meng
Cholestasis is a clinical syndrome with systemic and intrahepatic accumulation of excessive toxic bile acids that ultimately cause hepatobiliary injury. Recently obeticholic acid (OCA) which is a farnesoid X receptor (FXR) agonist was approved by FDA to treat cholestatic liver diseases, which provided us a newly therapeutic strategy against cholestasis. The purpose of the current study is to screen novel FXR agonists and verify the anti-cholestasis effect of yangonin in vivo and in vitro. The computational strategy of two-dimensional virtual screening was used to search for new FXR agonists, and dual-luciferase reporter gene assay was used to further demonstrate FXR activation by yangonin...
April 13, 2018: Toxicology and Applied Pharmacology
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