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https://www.readbyqxmd.com/read/28805978/obeticholic-acid-a-selective-farnesoid-x-receptor-agonist-regulates-bile-acid-homeostasis-in-sandwich-cultured-human-hepatocytes
#1
Yuanyuan Zhang, Jonathan P Jackson, Robert L St Claire, Kimberly Freeman, Kenneth R Brouwer, Jeffrey E Edwards
Farnesoid X receptor (FXR) is a master regulator of bile acid homeostasis through transcriptional regulation of genes involved in bile acid synthesis and cellular membrane transport. Impairment of bile acid efflux due to cholangiopathies results in chronic cholestasis leading to abnormal elevation of intrahepatic and systemic bile acid levels. Obeticholic acid (OCA) is a potent and selective FXR agonist that is 100-fold more potent than the endogenous ligand chenodeoxycholic acid (CDCA). The effects of OCA on genes involved in bile acid homeostasis were investigated using sandwich-cultured human hepatocytes...
August 2017: Pharmacology Research & Perspectives
https://www.readbyqxmd.com/read/28803504/the-pharmacological-management-of-nafld-in-children-and-adolescents
#2
Savinda Liyanagedera, Robert Patrick Williams, Silvio Veraldi, Valerio Nobili, Jake P Mann
Non-alcoholic fatty liver disease (NAFLD) represents a spectrum, including 'simple' steatosis, non-alcoholic steatohepatitis (NASH), and fibrosis. Increasing prevalence of NAFLD has followed the international rise in obesity and lifestyle modification is the mainstay therapy for children. To date, pharmacological trials have had varying efficacy but a large number of new agents are in early phase trials for adults. Areas covered: This review explores the effect of current and potential future paediatric NAFLD treatments in terms of histological and biochemical endpoints...
August 21, 2017: Expert Review of Clinical Pharmacology
https://www.readbyqxmd.com/read/28796169/cell-surface-and-nuclear-receptors-in-the-colon-as-targets-for-bacterial-metabolites-and-its-relevance-to-colon-health
#3
REVIEW
Sathish Sivaprakasam, Yangzom D Bhutia, Sabarish Ramachandran, Vadivel Ganapathy
The symbiotic co-habitation of bacteria in the host colon is mutually beneficial to both partners. While the host provides the place and food for the bacteria to colonize and live, the bacteria in turn help the host in energy and nutritional homeostasis, development and maturation of the mucosal immune system, and protection against inflammation and carcinogenesis. In this review, we highlight the molecular mediators of the effective communication between the bacteria and the host, focusing on selective metabolites from the bacteria that serve as messengers to the host by acting through selective receptors in the host colon...
August 10, 2017: Nutrients
https://www.readbyqxmd.com/read/28792854/phytosterols-synergize-with-endotoxin-to-augment-inflammation-in-kupffer-cells-but-alone-have-limited-direct-effect-on-hepatocytes
#4
Gregory Guthrie, Bryan Tackett, Barbara Stoll, Camilia Martin, Oluyinka Olutoye, Douglas G Burrin
INTRODUCTION: Phytosterols are implicated in the development of parenteral nutrition-associated liver disease. A newly proposed mechanism for phytosterol-mediated parenteral nutrition-associated liver disease is through phytosterol-facilitated hepatic proinflammatory cytokine release following exposure to intestinally derived bacteria. Whether the proinflammatory effects are liver cell specific is not known. AIM: To determine if phytosterols cause inflammation in hepatocytes or Kupffer cells independently or require costimulation by lipopolysaccharide (LPS)...
August 1, 2017: JPEN. Journal of Parenteral and Enteral Nutrition
https://www.readbyqxmd.com/read/28774887/suppressed-hepatic-bile-acid-signalling-despite-elevated-production-of-primary-and-secondary-bile-acids-in-nafld
#5
Na Jiao, Susan S Baker, Adrian Chapa-Rodriguez, Wensheng Liu, Colleen A Nugent, Maria Tsompana, Lucy Mastrandrea, Michael J Buck, Robert D Baker, Robert J Genco, Ruixin Zhu, Lixin Zhu
OBJECTIVE: Bile acids are regulators of lipid and glucose metabolism, and modulate inflammation in the liver and other tissues. Primary bile acids such as cholic acid and chenodeoxycholic acid (CDCA) are produced in the liver, and converted into secondary bile acids such as deoxycholic acid (DCA) and lithocholic acid by gut microbiota. Here we investigated the possible roles of bile acids in non-alcoholic fatty liver disease (NAFLD) pathogenesis and the impact of the gut microbiome on bile acid signalling in NAFLD...
August 3, 2017: Gut
https://www.readbyqxmd.com/read/28766097/ranking-docking-poses-by-graph-matching-of-protein-ligand-interactions-lessons-learned-from-the-d3r-grand-challenge-2
#6
Priscila da Silva Figueiredo Celestino Gomes, Franck Da Silva, Guillaume Bret, Didier Rognan
A novel docking challenge has been set by the Drug Design Data Resource (D3R) in order to predict the pose and affinity ranking of a set of Farnesoid X receptor (FXR) agonists, prior to the public release of their bound X-ray structures and potencies. In a first phase, 36 agonists were docked to 26 Protein Data Bank (PDB) structures of the FXR receptor, and next rescored using the in-house developed GRIM method. GRIM aligns protein-ligand interaction patterns of docked poses to those of available PDB templates for the target protein, and rescore poses by a graph matching method...
August 1, 2017: Journal of Computer-aided Molecular Design
https://www.readbyqxmd.com/read/28762281/clinical-significance-of-farnesoid-x-receptor-expression-in-thyroid-neoplasia
#7
Constantinos Giaginis, Nikolaos Tsoukalas, Paraskevi Alexandrou, Gerasimos Tsourouflis, Eugene Dana, Ioanna Delladetsima, Efstratios Patsouris, Stamatios Theocharis
AIM: To evaluate the clinical significance of farnesoid X receptor (FXR) in thyroid neoplasia. PATIENTS & METHODS: FXR expression was assessed immunohistochemically on 88 thyroid neoplastic tissues (benign = 44, malignant = 44). RESULTS: Enhanced FXR was more frequently observed in papillary carcinomas compared with hyperplastic nodules (p = 0.0489). In malignant lesions, elevated FXR was associated with capsular (p = 0.0004) and vascular invasion (p = 0...
August 1, 2017: Future Oncology
https://www.readbyqxmd.com/read/28749691/nonacidic-farnesoid-x-receptor-modulators
#8
Daniel Flesch, Sun-Yee Cheung, Jurema Schmidt, Matthias Gabler, Pascal Heitel, Jan Kramer, Astrid Kaiser, Markus Hartmann, Mara Lindner, Kerstin Lüddens-Dämgen, Jan Heering, Christina Lamers, Hartmut Lüddens, Mario Wurglics, Ewgenij Proschak, Manfred Schubert-Zsilavecz, Daniel Merk
As a cellular bile acid sensor, farnesoid X receptor (FXR) participates in regulation of bile acid, lipid and glucose homeostasis, and liver protection. Clinical results have validated FXR as therapeutic target in hepatic and metabolic diseases. To date, potent FXR agonists share a negatively ionizable function that might compromise their pharmacokinetic distribution and behavior. Here we report the development and characterization of a high-affinity FXR modulator not comprising an acidic residue.
August 8, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28749598/beyond-fxr-to-target-new-therapies-for-nafld
#9
EDITORIAL
Xiaoying Liu, Richard M Green
No abstract text is available yet for this article.
July 27, 2017: Hepatology: Official Journal of the American Association for the Study of Liver Diseases
https://www.readbyqxmd.com/read/28746779/hepatic-farnesoid-x-receptor-protein-level-and-circulating-fibroblast-growth-factor-19-concentration-in-children-with-nafld
#10
Valerio Nobili, Anna Alisi, Antonella Mosca, Claudia Della Corte, Silvio Veraldi, Rita De Vito, Cristiano De Stefanis, Valentina D'Oria, Joerg Jahnel, Evelyn Zohrer, Eleonora Scorletti, Christopher D Byrne
BACKGROUND & AIMS: Treatment with the farnesoid X receptor (FXR) agonist obeticholic acid is ineffective in some patients with non-alcoholic steatohepatitis (NASH) but the explanation is uncertain. We investigated hepatic FXR expression, and measurements of fibroblast growth factor 19 (FGF19) and bile acids (BAs) in children with NAFLD to investigate relationships with NASH. METHODS: 33 children with NAFLD who underwent diagnostic liver biopsy were studied. Hepatic FXR protein levels and circulating FGF19 concentrations were compared with those analyzed in five control subjects with proven normal liver histology...
July 26, 2017: Liver International: Official Journal of the International Association for the Study of the Liver
https://www.readbyqxmd.com/read/28739572/altenusin-a-non-steroidal-microbial-metabolite-attenuates-non-alcoholic-fatty-liver-disease-by-activating-the-farnesoid-x-receptor
#11
Zhihui Zheng, Zanmei Zhao, Shuqiang Li, Xinhua Lu, Mengxi Jiang, Jie Lin, Yunqi An, Yang Xie, Meishu Xu, Wenbin Shen, Grace Guo, YIxian Huang, Song Li, Xuexia Zhang, Wen Xie
Non-alcoholic fatty liver disease (NAFLD) is a prevalent chronic liver disease. The incidence of NAFLD has increased steadily due to its close association with the global epidemic of obesity and type 2 diabetes. However, there is no effective pharmacological therapy approved for NAFLD. Farnesoid X receptor (FXR), a member of the nuclear receptor subfamily, plays important roles in maintaining the homeostasis of bile acids, glucose and lipids. FXR agonists have shown promise for the treatment of NAFLD. Here we report Altenusin (2076A), a natural non-steroidal fungal metabolite, as a novel selective agonist of FXR with an EC50 value of 3...
July 24, 2017: Molecular Pharmacology
https://www.readbyqxmd.com/read/28734962/analyzing-the-hepatoprotective-effect-of-the-swertia-cincta-burkillextract-against-anit-induced-cholestasis-in-rats-by-modulating-the-expression-of-transporters-and-metabolic-enzymes
#12
Lili Xu, Tingting Sheng, Xiaolong Liu, Tong Zhang, Zhengtao Wang, Han Han
ETHNOPHARMACOLOGICAL RELEVANCE: Swertia cincta Burkill was traditionally used for treating jaundice and various types of chronic and acute hepatitis in Yunnan and Tibet in China for hundreds of years. This study aims to investigate the protective effect of S. cincta Burkill (ESC) extract on alpha-naphthylisothiocyanate (ANIT)-induced hepatotoxicity and cholestasis in rats. MATERIALS AND METHODS: Crude extracts were prepared using 90% ethanol and by vacuum drying...
July 19, 2017: Journal of Ethnopharmacology
https://www.readbyqxmd.com/read/28733267/angptl4-promotes-bile-acid-absorption-during-taurocholic-acid-supplementation-via-a-mechanism-dependent-on-the-gut-microbiota
#13
Aafke W F Janssen, Wieneke Dijk, Jos Boekhorst, Folkert Kuipers, Albert K Groen, Sabina Lukovac, Guido J E J Hooiveld, Sander Kersten
Angiopoietin-like 4 (ANGPTL4) raises plasma triglyceride levels by inhibiting lipoprotein lipase. A set of compounds that are able to reduce plasma triglyceride levels are bile acids (BA). Because BA have been shown to decrease ANGPTL4 secretion by intestinal cells, we hypothesized that BA lower plasma triglycerides (partly) via ANGPTL4. To test that hypothesis, wild-type and Angptl4(-/-) mice were fed chow supplemented with taurocholic acid (TCA) for seven days. TCA supplementation effectively lowered plasma triglycerides in wild-type and Angptl4(-/-) mice, indicating that ANGPTL4 is not required for plasma triglyceride-lowering by BA...
July 18, 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/28729691/lowered-fasting-chenodeoxycholic-acid-correlated-with-the-decrease-of-fibroblast-growth-factor-19-in-chinese-subjects-with-impaired-fasting-glucose
#14
Jing Zhang, Huating Li, Hu Zhou, Li Fang, Jingjing Xu, Han Yan, Shuqin Chen, Qianqian Song, Yinan Zhang, Aimin Xu, Qichen Fang, Yang Ye, Weiping Jia
The gut-derived hormone Fibroblast growth factor 19 (FGF19) could regulate glucose metabolism and is induced by bile acids (BAs) through activating Farnesoid X Receptor (FXR). FGF19 was found to decrease in subjects with isolated-impaired fasting glucose (I-IFG) and type 2 diabetes mellitus (T2DM). However, the reason for the change of FGF19 in subjects with different glucometabolic status remained unclear. Here we measured six BAs including chenodeoxycholic acid (CDCA), cholic acid, deoxycholic acid, their glycine conjugates and FGF19 levels during oral glucose tolerance test (OGTT) in normal glucose tolerance (NGT), isolated-impaired glucose tolerance, I-IFG, combined glucose intolerance (CGI) and T2DM subjects...
July 20, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28714273/%C3%AE-catenin-regulation-of-farnesoid-x-receptor-signaling-and-bile-acid-metabolism-during-murine-cholestasis
#15
Michael D Thompson, Akshata Moghe, Pamela Cornuet, Rebecca Marino, Jianmin Tian, Pengcheng Wang, Xiaochao Ma, Marc Abrams, Joseph Locker, Satdarshan P S Monga, Kari Nejak-Bowen
Cholestatic liver diseases result from impaired bile flow and are characterized by inflammation, atypical ductular proliferation (ADP), and fibrosis. The Wnt/β-catenin pathway plays a role in bile duct development, yet its role in cholestatic injury remains indeterminate. Liver-specific β-catenin knockout (KO) mice and wild-type (WT) littermates were subjected to cholestatic injury via bile duct ligation or short-term exposure to 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) diet. Intriguingly, KO exhibit a dramatic protection from liver injury, fibrosis, and ADP, which coincided with significantly decreased total hepatic bile acids (BA)...
July 17, 2017: Hepatology: Official Journal of the American Association for the Study of Liver Diseases
https://www.readbyqxmd.com/read/28711947/repression-of-intestinal-transporters-and-fxr-fgf15-signaling-explains-bile-acids-dysregulation-in-experimental-colitis-associated-colon-cancer
#16
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/28711154/western-diet-induced-dysbiosis-in-farnesoid-x-receptor-knockout-mice-causes-persistent-hepatic-inflammation-after-antibiotic-treatment
#17
Prasant K Jena, Lili Sheng, Hui-Xin Liu, Karen M Kalanetra, Annie Mirsoian, William J Murphy, Samuel W French, Viswanathan V Krishnan, David A Mills, Yu-Jui Yvonne Wan
Patients who have liver cirrhosis and liver cancer also have reduced farnesoid X receptor (FXR). The current study analyzes the effect of diet through microbiota that affect hepatic inflammation in FXR knockout (KO) mice. Wild-type and FXR KO mice were on a control (CD) or Western diet (WD) for 10 months. In addition, both CD- and WD-fed FXR KO male mice, which had hepatic lymphocyte and neutrophil infiltration, were treated by vancomycin, polymyxin B, and Abx (ampicillin, neomycin, metronidazole, and vancomycin)...
August 2017: American Journal of Pathology
https://www.readbyqxmd.com/read/28709961/bile-acids-fgf15-19-and-liver-regeneration-from-mechanisms-to-clinical-applications
#18
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/28706193/polydextrose-changes-the-gut-microbiome-and-attenuates-fasting-triglyceride-and-cholesterol-levels-in-western-diet-fed-mice
#19
Ghulam Shere Raza, Heli Putaala, Ashley A Hibberd, Esa Alhoniemi, Kirsti Tiihonen, Kari Antero Mäkelä, Karl-Heinz Herzig
Obesity and dyslipidemia are hallmarks of metabolic and cardiovascular diseases. Polydextrose (PDX), a soluble fiber has lipid lowering effects. We hypothesize that PDX reduces triglycerides and cholesterol by influencing gut microbiota, which in turn modulate intestinal gene expression. C57BL/6 male mice were fed a Western diet (WD) ±75 mg PDX twice daily by oral gavage for 14 days. Body weight and food intake were monitored daily. Fasting plasma lipids, caecal microbiota and gene expression in intestine and liver were measured after 14 days of feeding...
July 13, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28702667/microengineered-cultures-containing-human-hepatic-stellate-cells-and-hepatocytes-for-drug-development
#20
Matthew D Davidson, David A Kukla, Salman R Khetani
In non-alcoholic steatohepatitis (NASH), hepatic stellate cells (HSC) differentiate into myofibroblast-like cells that cause fibrosis, which predisposes patients to cirrhosis and hepatocellular carcinoma. Thus, modeling interactions between activated HSCs and hepatocytes in vitro can aid in the development of anti-NASH/fibrosis therapeutics and lead to a better understanding of disease progression. Species-specific differences in drug metabolism and disease pathways now necessitate the supplementation of animal studies with data acquired using human liver models; however, current models do not adequately model the negative effects of primary human activated HSCs on the phenotype of otherwise well-differentiated primary human hepatocytes (PHHs) as in vivo...
August 14, 2017: Integrative Biology: Quantitative Biosciences From Nano to Macro
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