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Farnesoid x receptor

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https://www.readbyqxmd.com/read/28195307/effect-of-obeticholic-acid-on-liver-regeneration-following-portal-vein-embolization-in-an-experimental-model
#1
P B Olthof, F Huisman, F G Schaap, K P van Lienden, R J Bennink, R F van Golen, M Heger, J Verheij, P L Jansen, S W Olde Damink, T M van Gulik
BACKGROUND: The bile salt-activated transcription factor farnesoid X receptor (FXR) is a key mediator of proliferative bile salt signalling, which is assumed to play a role in the early phase of compensatory liver growth. The aim of this study was to evaluate the effect of a potent FXR agonist (obeticholic acid, OCA) on liver growth following portal vein embolization (PVE). METHODS: Rabbits were allocated to receive daily oral gavage with OCA (10 mg/kg) or vehicle (control group) starting 7 days before PVE (n = 18 per group), and continued until 7 days after PVE...
February 13, 2017: British Journal of Surgery
https://www.readbyqxmd.com/read/28192885/polyphenols-rich-passiflora-leschenaultii-leaves-modulating-farnesoid-x-receptor-and-pregnane-x-receptor-against-paracetamol-induced-hepatotoxicity-in-rats
#2
Saravanan Shanmugam, Dhivya Sivaraj, Bruno Dos Santos Lima, Paula Dos Passos Menezes, Yasmim Maria Barbosa Gomes de Carvalho, Adriano Antunes de Souza Araújo, Narendra Narain, Mairim Russo Serafini, Lucindo José Quintans Júnior, Luciana Scotti, Marcus Tulius Scotti, Thangaraj Parimelazhagan
The hepatoprotective effect of P. leschenaultii. (DC) leaves was investigated in rats under paracetamol induced oxidative stress. Leaf acetone extract (200 and 400mg/kg) were administered daily via gavage for 14days before paracetamol (2000mg/kg, p.o.) treatment. After the experiment, the levels of serum biochemical parameters and enzymatic antioxidant levels were determined. Furthermore, liver tissues were analyzed histopathologically. Additionally, the molecular docking studies of the identified compounds against PXR and FXR proteins were also performed...
February 9, 2017: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
https://www.readbyqxmd.com/read/28190654/discovery-and-optimization-of-benzimidazole-derivatives-as-a-novel-chemotype-of-farnesoid-x-receptor-fxr-antagonists
#3
Naoki Teno, Yusuke Iguchi, Yukiko Yamashita, Nobuhiro Mori, Mizuho Une, Tomoko Nishimaki-Mogami, Keigo Gohda
We describe here a novel chemotype with substituted benzimidazole scaffold for nonsteroidal farnesoid X receptor (FXR) antagonists starting from the identification of a screening hit, BB-4. Structure diversity in four regions A-D of BB-4 or 1 is discussed. In particular, regions A and C had an effect on an antagonism against FXR as demonstrated by the derivatives represented by 7 and 15, respectively. Thus, compound 19 arising from the combination of regions A and C underscored an important fact on antagonism against FXR, also showing the reduced small heterodimer partner and the increased cholesterol 7α-hydroxylase expression levels...
January 31, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/28190475/calycosin-attenuates-triglyceride-accumulation-and-hepatic-fibrosis-in-murine-model-of-non-alcoholic-steatohepatitis-via-activating-farnesoid-x-receptor
#4
Xingping Duan, Qiang Meng, Changyuan Wang, Zhihao Liu, Qi Liu, Huijun Sun, Pengyuan Sun, Xiaobo Yang, Xiaokui Huo, Jinyong Peng, Kexin Liu
BACKGROUND: Non-alcoholic steatohepatitis (NASH) represents the more severe end of hepatic steatosis and is associated with progressive liver disease. Calycosin, derived from the root of Radix Astragali, has been demonstrated to have favorable efficacy on acute liver injury. PURPOSE: The present study was to investigate the hepatoprotective effect of calycosin on attenuating triglyceride accumulation and hepatic fibrosis, as well as explore the potential mechanism in murine model of NASH...
February 15, 2017: Phytomedicine: International Journal of Phytotherapy and Phytopharmacology
https://www.readbyqxmd.com/read/28187366/a-combination-of-dietary-n-3-fatty-acids-and-a-cyclooxygenase-1-inhibitor-attenuates-nonalcoholic-fatty-liver-disease-in-mice
#5
Viswanathan Saraswathi, Curtis Perriotte-Olson, Murali Ganesan, Cyrus V Desouza, Yazen Alnouti, Michael J Duryee, Geoffrey M Thiele, Tara M Nordgren, Dahn L Clemens
We sought to determine whether a combination of purified n-3 fatty acids (n-3) and SC-560 (SC), a cyclooxygenase-1-specific inhibitor, is effective in ameliorating nonalcoholic fatty liver disease in obesity. Female wild-type mice were fed a high-fat and high-cholesterol diet (HF) supplemented with n-3 in the presence or absence of SC. Mice treated with SC alone exhibited no change in liver lipids, whereas n-3-fed mice tended to have lower hepatic lipids. Mice given n-3+SC had significantly lower liver lipids compared with HF controls indicating enhanced lipid clearance...
January 27, 2017: Journal of Nutritional Biochemistry
https://www.readbyqxmd.com/read/28186695/a-novel-class-of-natural-fxr-modulators-with-a-unique-mode-of-selective-coregulator-assembly
#6
Weili Zheng, Yi Lu, Shengchen Lin, Rui Wang, Lin Qiu, Yanlin Zhu, Benqiang Yao, Fusheng Guo, Shikai Jin, Lihua Jin, Yong Li
Farnesoid X receptor (FXR) is an important target for drug discovery. Small molecules induce the conformational change of FXR that modulates its binding to coregulators, resulting in distinctive functional profiles of FXR. However, the mechanisms for selectively recruiting coregulators by FXR remain elusive, partly due to the lack of FXR selective modulators. We report here the identification of two natural terpenoids, tschimgine and feroline, as a novel class of FXR modulators. Remarkably, crystal structures uncover a secondary binding-induced pocket important for ligand binding...
February 10, 2017: Chembiochem: a European Journal of Chemical Biology
https://www.readbyqxmd.com/read/28185763/bariatric-surgery-attenuates-colitis-in-an-obese-murine-model
#7
Shiri Li, Alessio Vinci, Judith Behnsen, Chunmei Cheng, Stefan Jellbauer, Manuela Raffatellu, Kyle M Sousa, Robert Edwards, Ninh T Nguyen, Michael J Stamos, Alessio Pigazzi
BACKGROUND: Obesity and inflammatory bowel disease (IBD) represent chronic inflammatory conditions. Bariatric surgery improves some obesity-related co-morbidities, but the effects of bariatric surgery on IBD have not been well studied. OBJECTIVES: To examine if bariatric surgery may attenuate colitis in an obese murine model of IBD and study the mechanisms underlying the postsurgical amelioration of intestinal inflammation. SETTING: University of California Irvine, Department of Surgery and Microbiology laboratories...
December 20, 2016: Surgery for Obesity and related Diseases: Official Journal of the American Society for Bariatric Surgery
https://www.readbyqxmd.com/read/28178326/quantitative-liver-proteomics-identifies-fgf19-targets-that-couple-metabolism-and-proliferation
#8
Vittoria Massafra, Alexandra Milona, Harmjan R Vos, Boudewijn M T Burgering, Saskia W C van Mil
Fibroblast growth factor 19 (FGF19) is a gut-derived peptide hormone that is produced following activation of Farnesoid X Receptor (FXR). FGF19 is secreted and signals to the liver, where it contributes to the homeostasis of bile acid (BA), lipid and carbohydrate metabolism. FGF19 is a promising therapeutic target for the metabolic syndrome and cholestatic diseases, but enthusiasm for its use has been tempered by FGF19-mediated induction of proliferation and hepatocellular carcinoma. To inform future rational design of FGF19-variants, we have conducted temporal quantitative proteomic and gene expression analyses to identify FGF19-targets related to metabolism and proliferation...
2017: PloS One
https://www.readbyqxmd.com/read/28174746/the-farnesoid-x-receptor-good-for-bad
#9
REVIEW
Stephen J Keely, Julian R F Walters
Diarrhea is a feature of several chronic intestinal disorders that are associated with increased delivery of bile acids into the colon. Although the prevalence of bile acid diarrhea is high, affecting approximately 1% of the adult population, current therapies often are unsatisfactory. By virtue of its capacity to inhibit colonic epithelial fluid secretion and to down-regulate hepatic bile acid synthesis through induction of the ileal fibroblast growth factor 19 release, the nuclear bile acid receptor, farnesoid X receptor, represents a promising target for the development of new therapeutic approaches...
November 2016: Cellular and Molecular Gastroenterology and Hepatology
https://www.readbyqxmd.com/read/28169840/bile-acid-disease-the-emerging-epidemic
#10
Ibironke Oduyebo, Michael Camilleri
PURPOSE OF REVIEW: Our objective was to review advances in bile acids in health and disease published in the last 2 years. Bile acid diarrhea (BAD) is recognized as a common cause of chronic diarrhea, and its recognition has been facilitated by development of new screening tests. RECENT FINDINGS: Primary BAD can account for 30% of cases of chronic diarrhea. The mechanisms leading to BAD include inadequate feedback regulation by fibroblast growth factor 19 (FGF-19) from ileal enterocytes, abnormalities in synthesis or degradation of proteins involved in FGF-19 regulation in hepatocytes and variations as a function of the bile acid receptor, TGR5 (GPBAR1)...
February 6, 2017: Current Opinion in Gastroenterology
https://www.readbyqxmd.com/read/28165466/tauroursodeoxycholic-acid-protects-bile-acid-homeostasis-under-inflammatory-conditions-and-dampens-crohn-s-disease-like-ileitis
#11
Lien Van den Bossche, Daniel Borsboom, Sarah Devriese, Sophie Van Welden, Tom Holvoet, Lindsey Devisscher, Pieter Hindryckx, Martine De Vos, Debby Laukens
Bile acids regulate the expression of intestinal bile acid transporters and are natural ligands for nuclear receptors controlling inflammation. Accumulating evidence suggests that signaling through these receptors is impaired in inflammatory bowel disease. We investigated whether tauroursodeoxycholic acid (TUDCA), a secondary bile acid with cytoprotective properties, regulates ileal nuclear receptor and bile acid transporter expression and assessed its therapeutic potential in an experimental model of Crohn's disease (CD)...
February 6, 2017: Laboratory Investigation; a Journal of Technical Methods and Pathology
https://www.readbyqxmd.com/read/28164071/transcriptional-coordination-of-hepatic-autophagy-by-nutrient-sensing-nuclear-receptor-ppar%C3%AE-and-fxr
#12
REVIEW
Jae Man Lee
Nuclear receptors are in general ligand-dependent transcription factors that control a variety of mammalian physiologies including development, differentiation, proliferation, and homeostasis. Recent studies have found that two nutrient-sensing nuclear receptors, peroxisome proliferator-activated receptor α and farnesoid x receptor, responding to fasting or feeding state, respectively are able to regulate autophagy, an evolutionarily conserved catabolic process involved in lysosomal degradation. In this review, we discuss the role of these nutrient-sensing nuclear receptors in an aspect of transcriptional regulation of autophagy, and how these nuclear receptor-driven transcriptional programs integrate lipophagy, a lipid autophagy with fatty acid oxidation to coordinate hepatic lipid metabolism in the fasted state of the liver...
December 2016: Annals of Pediatric Endocrinology & Metabolism
https://www.readbyqxmd.com/read/28153708/steroidogenic-acute-regulatory-protein-star-overexpression-attenuates-hfd-induced-hepatic-steatosis-and-insulin-resistance
#13
Yanyan Qiu, Xianxian Sui, Yongkun Zhan, Chen Xu, Xiaobo Li, Yanxia Ning, Xiuling Zhi, Lianhua Yin
Non-alcoholic fatty liver disease (NAFLD) covers a wide spectrum of liver pathology. Intracellular lipid accumulation is the first step in the development and progression of NAFLD. Steroidogenic acute regulatory protein (StAR) plays an important role in the synthesis of bile acid and intracellular lipid homeostasis and cholesterol metabolism. We hypothesize that StAR is involved in non-alcoholic fatty liver disease (NAFLD) pathogenesis. The hypothesis was identified using free fatty acid (FFA)-overloaded NAFLD in vitro model and high-fat diet (HFD)-induced NAFLD mouse model transfected by recombinant adenovirus encoding StAR (StAR)...
January 30, 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/28145001/treatment-with-the-natural-fxr-agonist-chenodeoxycholic-acid-reduces-clearance-of-plasma-ldl-whilst-decreasing-circulating-pcsk9-lipoprotein-a-and-apolipoprotein-c-iii
#14
M Ghosh Laskar, M Eriksson, M Rudling, B Angelin
BACKGROUND: The natural farnesoid X receptor (FXR) agonist chenodeoxycholic acid (CDCA) suppresses hepatic cholesterol and bile acid synthesis and reduces biliary cholesterol secretion and triglyceride production. Animal studies have shown that bile acids downregulate hepatic LDL receptors (LDLRs); however, information on LDL metabolism in humans is limited. METHODS: Kinetics of autologous (125) I-LDL were determined in 12 male subjects at baseline and during treatment with CDCA (15 mg kg(-1) day(-1) )...
February 1, 2017: Journal of Internal Medicine
https://www.readbyqxmd.com/read/28130067/farnesoid-x-receptor-activation-promotes-hepatic-amino-acid-catabolism-and-ammonium-clearance-in-mice
#15
Vittoria Massafra, Alexandra Milona, Harmjan R Vos, Rúben J J Ramos, Johan Gerrits, Ellen C L Willemsen, José M Ramos Pittol, Noortje Ijssennagger, Martin Houweling, Hubertus C M T Prinsen, Nanda M Verhoeven-Duif, Boudewijn M Burgering, Saskia W C van Mil
BACKGROUND & AIMS: The nuclear receptor subfamily 1 group H member 4 (NR1H4 or farnesoid X receptor, FXR) regulates bile acid synthesis, transport, and catabolism. FXR also regulates post-prandial lipid and glucose metabolism. We performed quantitative proteomic analyses of liver tissues from mice to evaluate these functions and investigate whether FXR regulates amino acid metabolism. METHODS: To study the role of FXR in mouse liver, we used mice with a disruption of Nr1h4 (FXR-knockout mice) and compared them to floxed control mice...
January 24, 2017: Gastroenterology
https://www.readbyqxmd.com/read/28125709/differential-feedback-regulation-of-%C3%AE-4-3-oxosteroid-5%C3%AE-reductase-expression-by-bile-acids
#16
Leila Valanejad, Christina Nadolny, Stephanie Shiffka, Yuan Chen, Sangmin You, Ruitang Deng
Δ4-3-oxosteroid 5β-reductase is member D1 of the aldo-keto reductase family 1 (AKR1D1), which catalyzes 5β-reduction of molecules with a 3-oxo-4-ene structure. Bile acid intermediates and most of the steroid hormones carry the 3-oxo-4-ene structure. Therefore, AKR1D1 plays critical roles in both bile acid synthesis and steroid hormone metabolism. Currently our understanding on transcriptional regulation of AKR1D1 under physiological and pathological conditions is very limited. In this study, we investigated the regulatory effects of primary bile acids, chenodeoxycholic acid (CDCA) and cholic acid (CA), on AKR1D1 expression...
2017: PloS One
https://www.readbyqxmd.com/read/28120707/farnesoid-x-receptor-fxr-as-a-promising-pharmaceutical-target-in-atherosclerosis
#17
Demetrios Moris, Constantinos Giaginis, Gerasimos Tsourouflis, Stamatios Theocharis
BACKGROUND: Atherosclerosis (AS) is a major cause of death and morbidity in Western world and is strongly connected with atherogenic lipoproteins and inflammation. Bile acids (BA) act as activating signals of endogenous ligands such as Farnesoid-X receptor (FXR). Primary data indicate a potential role of FXR in AS. The therapeutic value of FXR ligands in AS is unknown. OBJECTIVE: With the present review we analyzed the efficacy of FXR agonists as a therapeutic modalities against AS...
January 24, 2017: Current Medicinal Chemistry
https://www.readbyqxmd.com/read/28115235/anti-fibrotic-effects-of-chronic-treatment-with-the-selective-fxr-agonist-obeticholic-acid-in-the-bleomycin-induced-rat-model-of-pulmonary-fibrosis
#18
Paolo Comeglio, Sandra Filippi, Erica Sarchielli, Annamaria Morelli, Ilaria Cellai, Francesca Corcetto, Chiara Corno, Elena Maneschi, Alessandro Pini, Luciano Adorini, Gabriella Barbara Vannelli, Mario Maggi, Linda Vignozzi
Farnesoid X receptor (FXR) activation by obeticholic acid (OCA) has been demonstrated to inhibit inflammation and fibrosis development in liver, kidney and intestine in multiple disease models. FXR activation has also been demonstrated to suppress the inflammatory response and to promote lung repair after lung injury. This study investigated the protective effects of OCA treatment (3 or 10mg/kg/day) on inflammation, tissue remodeling and fibrosis in the bleomycin-induced pulmonary fibrosis rat model. Effects of OCA treatment on morphological and molecular alterations of the lung, as well as remodeling of the alveoli and the right ventricle were also evaluated...
January 20, 2017: Journal of Steroid Biochemistry and Molecular Biology
https://www.readbyqxmd.com/read/28111285/the-interrelationship-between-bile-acid-and-vitamin-a-homeostasis
#19
REVIEW
Ali Saeed, Mark Hoekstra, Martijn Oscar Hoeke, Janette Heegsma, Klaas Nico Faber
Vitamin A is a fat-soluble vitamin important for vision, reproduction, embryonic development, cell differentiation, epithelial barrier function and adequate immune responses. Efficient absorption of dietary vitamin A depends on the fat-solubilizing properties of bile acids. Bile acids are synthesized in the liver and maintained in an enterohepatic circulation. The liver is also the main storage site for vitamin A in the mammalian body, where an intimate collaboration between hepatocytes and hepatic stellate cells leads to the accumulation of retinyl esters in large cytoplasmic lipid droplet hepatic stellate cells...
January 19, 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/28102638/farnesoid-x-receptor-ablation-sensitizes-mice-to-hepatitis-b-virus-x-protein-induced-hepatocarcinogenesis
#20
Yongdong Niu, Meishu Xu, Betty L Slagle, Haihua Huang, Song Li, Grace L Guo, Ganggang Shi, Wenxin Qin, Wen Xie
: Chronic hepatitis B virus infection is a major risk factor for hepatocellular carcinoma (HCC). Hepatitis B virus X protein (HBx) is a hepatitis B virus protein that has multiple cellular functions, but its role in HCC pathogenesis has been controversial. Farnesoid X receptor (FXR) is a nuclear receptor with activities in anti-inflammation and inhibition of hepatocarcinogenesis. However, whether or how FXR can impact hepatitis B virus/HBx-induced hepatocarcinogenesis remains unclear...
November 5, 2016: Hepatology: Official Journal of the American Association for the Study of Liver Diseases
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