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https://www.readbyqxmd.com/read/29665350/pxr-structure-specific-activation-by-hepatotoxic-pyrrolizidine-alkaloids
#1
Claudia Luckert, Albert Braeuning, Alfonso Lampen, Stefanie Hessel-Pras
Pyrrolizidine alkaloids (PAs) comprise a large group of more than 660 secondary metabolites found in more than 6000 plant species worldwide. Acute PA intoxication induces severe liver damage. Chronic exposure to sub-lethal doses may cause cumulative damage or cancer. Nuclear receptor activation often constitutes a molecular event for xenobiotic-induced toxicity. However, so far nothing is known about potential interactions of PAs with nuclear receptors as a toxicological mode of action. Thus, in the present study PA-dependent activation of a comprehensive panel of nuclear receptors (PPARs, LXRα, RARα, RXRα, FXR, CAR, PXR, ERα/β) was investigated using GAL4/UAS-based transactivation reporter gene assays...
April 14, 2018: Chemico-biological Interactions
https://www.readbyqxmd.com/read/29660435/yangonin-protects-against-cholestasis-and-hepatotoxity-via-activation-of-farnesoid-x-receptor-in-vivo-and-in-vitro
#2
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
https://www.readbyqxmd.com/read/29655695/alisma-orientale-extract-exerts-the-reversing-cholestasis-effect-by-activation-of-farnesoid-x-receptor
#3
Xiao-Kui Huo, Jing Liu, Zhen-Long Yu, Yi-Fei Wang, Chao Wang, Xiang-Ge Tian, Jing Ning, Lei Feng, Cheng-Peng Sun, Bao-Jing Zhang, Xiao-Chi Ma
BACKGROUND: Cholestasis is a clinical syndrome of liver damage that is caused by accumulation of bile acids in the liver and systemic circulation. Farnesoid X receptor (FXR) can regulate synthesis, metabolism, and excretion of bile acids. The rhizomes of Alisma orientale is a well-known traditional Chinese medicine to treat edema, obesity, gonorrhea, leukorrhea, diarrhea, hyperlipidemia, and diabetes in China. HYPOTHESIS/PURPOSE: We hypothesized Alisma orientale extract (AOE) to exert hepatoprotective effect against α-naphthylisothiocyanate (ANIT) induced cholestasis in rat...
March 15, 2018: Phytomedicine: International Journal of Phytotherapy and Phytopharmacology
https://www.readbyqxmd.com/read/29651702/tsumura-suzuki-obese-diabetic-mice-derived-hepatic-tumors-closely-resemble-human-hepatocellular-carcinomas-in-metabolism-related-genes-expression-and-bile-acid-accumulation
#4
Tetsuyuki Takahashi, Ulrich Deuschle, Shu Taira, Takeshi Nishida, Makoto Fujimoto, Takao Hijikata, Koichi Tsuneyama
BACKGROUND AND AIMS: Tsumura-Suzuki obese diabetic (TSOD) is a good model of metabolic syndrome showing typical lesions found in nonalcoholic fatty liver disease and nonalcoholic steatohepatitis, and develops spontaneous hepatic tumors with a high frequency. Majority of the developing tumors overexpress glutamine synthetase (GS), which is used as a marker of hepatocellular carcinoma (HCC). The aim of this study is to assess the status of expression of metabolism-related genes and the level of bile acids in the TSOD mice-derived tumors and to determine the association with metabolic dysregulation between human HCC and TSOD mice-derived tumors...
April 12, 2018: Hepatology International
https://www.readbyqxmd.com/read/29649907/farnesoid-x-receptor-modulators-2014-present-a-patent-review
#5
Valentina Sepe, Eleonora Distrutti, Stefano Fiorucci, Angela Zampella
The nuclear receptor FXR regulates the expression of genes involved in bile acids, glucose and lipid homeostasis. For its role as guardian of metabolism, FXR has been identified a promising pharmacological target in liver bile acid and lipid accumulation, such as cholestasis and non-alcoholic fatty liver disease (NAFLD). The field of FXR research is extremely competitive with a large number of patents and articles published in the last decades identifying promising hit compounds. Areas covered. The present review summarizes recent patent activity (2014-to date) filing for synthetic and natural FXR ligands, including bile acid derivatives and non-steroidal compounds, alongside their in vitro and in vivo efficacy as well as their therapeutic applications...
April 13, 2018: Expert Opinion on Therapeutic Patents
https://www.readbyqxmd.com/read/29582208/update-on-bile-acid-malabsorption-finally-ready-for-prime-time
#6
REVIEW
Priya Vijayvargiya, Michael Camilleri
PURPOSE OF REVIEW: To provide an update on the prevalence, pathophysiology, disease associations, and treatment options for bile acid malabsorption (BAM). RECENT FINDINGS: •Molecular mechanisms-BAs prevent water reabsorption and increase water secretion by intracellular mediators, increasing aquaporin channels and intracellular permeability. •Inflammatory bowel disease-new molecular mechanisms of BAM are identified in patients without ileal disease, including changes in expression of ileal BA transporter and nuclear receptors involved in BA homeostasis...
March 26, 2018: Current Gastroenterology Reports
https://www.readbyqxmd.com/read/29577938/hs218-as-an-fxr-antagonist-suppresses-gluconeogenesis-by-inhibiting-fxr-binding-to-pgc-1%C3%AE-promoter
#7
Xin Xu, Xiaofan Shi, Yidi Chen, Tingting Zhou, Jiaying Wang, Xing Xu, Lili Chen, Lihong Hu, Xu Shen
INTRODUCTION: Farnesoid X receptor (FXR) as a member of nuclear receptor is tightly associated with glucose metabolism. Accumulated evidence has addressed the potential of FXR antagonist in the treatment of type 2 diabetes mellitus (T2DM), although the related mechanisms remain unclear. Here, we determined a specific FXR antagonist HS218 (N-benzyl-N-(3-(tert-butyl)-4-hydroxyphenyl)-2,4-dichlorobenzamide), which exhibited high activities in suppressing gluconeogenesis and ameliorating glucose homeostasis in db/db and HFD/STZ-induced T2DM mice...
March 22, 2018: Metabolism: Clinical and Experimental
https://www.readbyqxmd.com/read/29569377/immune-regulation-by-microbiome-metabolites
#8
REVIEW
Chang H Kim
Commensal microbes and the host immune system have been co-evolved for mutual regulation. Microbes regulate the host immune system, in part, by producing metabolites. A mounting body of evidence indicates that diverse microbial metabolites profoundly regulate the immune system via host receptors and other target molecules. Immune cells express metabolite-specific receptors such as P2X7 , GPR41, GPR43, GPR109A, aryl hydrocarbon receptor precursor (AhR), pregnane X receptor (PXR), farnesoid X receptor (FXR), TGR5 and other molecular targets...
March 22, 2018: Immunology
https://www.readbyqxmd.com/read/29559521/fxr-activation-by-obeticholic-acid-or-non-steroidal-agonists-induces-a-human-like-lipoprotein-cholesterol-change-in-mice-with-humanized-chimeric-liver
#9
Romeo Papazyan, Xueqing Liu, Jingwen Liu, Bin Dong, Emily M Plummer, Ronald D Lewis, Jonathan D Roth, Mark A Young
Obeticholic acid (OCA) is a selective farnesoid X receptor (FXR) agonist that regulates bile acid and lipid metabolism. FXR activation induces distinct changes in circulating cholesterol among animal models and humans. The mechanistic basis of these effects has been elusive because of difficulties in studying lipoprotein homeostasis in mice, which predominantly package circulating cholesterol in high-density lipoproteins. Here, we tested the effects of OCA in chimeric mice whose livers are mostly composed (≥80%) of human hepatocytes...
March 20, 2018: Journal of Lipid Research
https://www.readbyqxmd.com/read/29553998/new-insights-in-the-multiple-roles-of-bile-acids-and-their-signaling-pathways-in-metabolic-control
#10
Jan F de Boer, Vincent W Bloks, Esther Verkade, M Rebecca Heiner-Fokkema, Folkert Kuipers
PURPOSE OF REVIEW: There is a growing awareness that individual bile acid species exert different physiological functions, beyond their classical roles in bile formation and fat absorption, due to differential stimulatory effects on the bile-acid-activated receptors farnesoid X receptor (FXR) and takeda G receptor 5 (TGR5). This review integrates recent findings on the role of individual bile acids and their receptors in metabolic control, with special emphasis on cholesterol homeostasis...
March 16, 2018: Current Opinion in Lipidology
https://www.readbyqxmd.com/read/29548878/natural-products-as-modulators-of-the-nuclear-receptors-and-metabolic-sensors-lxr-fxr-and-rxr
#11
REVIEW
Verena Hiebl, Angela Ladurner, Simone Latkolik, Verena M Dirsch
Nuclear receptors (NRs) represent attractive targets for the treatment of metabolic syndrome-related diseases. In addition, natural products are an interesting pool of potential ligands since they have been refined under evolutionary pressure to interact with proteins or other biological targets. This review aims to briefly summarize current basic knowledge regarding the liver X (LXR) and farnesoid X receptors (FXR) that form permissive heterodimers with retinoid X receptors (RXR). Natural product-based ligands for these receptors are summarized and the potential of LXR, FXR and RXR as targets in precision medicine is discussed...
March 13, 2018: Biotechnology Advances
https://www.readbyqxmd.com/read/29541476/antidyslipidemic-potential-of-a-novel-farnesoid-x-receptor-antagonist-in-a-hamster-model-of-dyslipidemia-comparative-studies-of-other-nonstatin-agents
#12
Emiko Shinozawa, Yuichiro Amano, Hiroko Yamakawa, Megumi Haba, Mitsuyuki Shimada, Ryuichi Tozawa
We attempted to clarify the therapeutic capability of antagonists of the farnesoid X receptor (FXR), a nuclear receptor that regulates lipid and bile acid metabolism. Herein, we report the antidyslipidemic effects of a novel synthesized FXR antagonist, compound-T1, utilizing a dyslipidemic hamster model. Compound-T1 selectively inhibited chenodeoxycholic acid-induced FXR activation (IC50 , 2.1 nmol·L-1 ). A hamster model of diet-induced hyperlipidemia was prepared to investigate the antidyslipidemic effects of compound-T1 through comparative studies of the nonstatin lipid-modulating agents ezetimibe, cholestyramine, and torcetrapib...
April 2018: Pharmacology Research & Perspectives
https://www.readbyqxmd.com/read/29530598/disruption-of-tfg%C3%AE-smad3-pathway-by-the-nuclear-receptor-shp-mediates-the-antifibrotic-activities-of-bar704-a-novel-highly-selective-fxr-ligand
#13
Adriana Carino, Michele Biagioli, Silvia Marchianò, Paolo Scarpelli, Angela Zampella, Vittorio Limongelli, Stefano Fiorucci
Liver fibrosis, a major health concern worldwide, results from abnormal collagen deposition by activated hepatic stellate cells (HSCs) in a injured liver. The farnesoid-x-receptor (FXR) is a bile acid sensor that counteracts HSCs transdifferentiation. While targeting FXR holds promise, 6-ethyl-CDCA known as obeticholic acid, the first in class of FXR ligands, causes side effects, partially because the lack of selectivity toward GPBAR1, a putative itching receptor. Here, we describe the 3-deoxy-6-ethyl derivative of CDCA, BAR704, as a highly selective steroidal FXR agonist...
March 9, 2018: Pharmacological Research: the Official Journal of the Italian Pharmacological Society
https://www.readbyqxmd.com/read/29507904/improved-oxygenation-dramatically-alters-metabolism-and-gene-expression-in-cultured-primary-mouse-hepatocytes
#14
Eduardo H Gilglioni, Jung-Chin Chang, Suzanne Duijst, Simei Go, Aziza A A Adam, Ruurdtje Hoekstra, Arthur J Verhoeven, Emy L Ishii-Iwamoto, Ronald P J Oude Elferink
Primary hepatocyte culture is an important in vitro system for the study of liver functions. In vivo , hepatocytes have high oxidative metabolism. However, oxygen supply by means of diffusion in in vitro static cultures is much less than that by blood circulation in vivo . Therefore, we investigated whether hypoxia contributes to dedifferentiation and deregulated metabolism in cultured hepatocytes. To this end, murine hepatocytes were cultured under static or shaken (60 revolutions per minute) conditions in a collagen sandwich...
March 2018: Hepatology Communications
https://www.readbyqxmd.com/read/29500352/concurrent-mir-21-suppression-and-fxr-activation-as-a-mechanism-of-improvement-in-nonalcoholic-fatty-liver-disease
#15
Guilherme S Mazzini, Jad Khoraki, Matthew G Browning, Guilherme M Campos
No abstract text is available yet for this article.
March 2, 2018: Cell Death & Disease
https://www.readbyqxmd.com/read/29491146/mice-lacking-arv1-have-reduced-signs-of-metabolic-syndrome-and-non-alcoholic-fatty-liver-disease
#16
Christina Gallo-Ebert, Jamie Francisco, Hsing-Yin Liu, Riley Draper, Kinnari Modi, Michael D Hayward, Beverly K Jones, Olesia Buiakova, Virginia McDonough, Joseph T Nickels
MetS syndrome (MetS) is a term used to characterize individuals having at least three of the following diseases: obesity, dyslipidemia, hyperglycemia, insulin resistance, hypertension, and non-alcoholic fatty liver disease (NAFLD).  It is widespread and the number of individuals with MetS is increasing.  However, the events leading to the manifestation of MetS are not well understood.  Here, we show that loss of mARV1 in mice results in resistance to acquiring diseases associated with MetS.   Arv1-/- animals fed a high fat diet were resistant to diet-induced obesity, had lower blood cholesterol and triglycerides levels, and retained glucose tolerance and insulin sensitivity...
February 28, 2018: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/29487110/fxr-agonists-obeticholic-acid-and-chenodeoxycholic-acid-increase-bile-acid-efflux-in-sandwich-cultured-human-hepatocytes-functional-evidence-and-mechanisms
#17
Cen Guo, Carl LaCerte, Jeffrey E Edwards, Kenneth R Brouwer, Kim L R Brouwer
Farnesoid X Receptor (FXR) is a nuclear receptor that regulates genes involved in bile acid homeostasis. FXR agonists, obeticholic acid (OCA) and chenodeoxycholic acid (CDCA), increase mRNA expression of efflux transporters in sandwich-cultured human hepatocytes (SCHH). This study evaluated the effects of OCA and CDCA treatment on the uptake, basolateral efflux, and biliary excretion of a model bile acid, taurocholate (TCA), in SCHH. Additionally, changes in the protein expression of TCA uptake and efflux transporters were investigated...
February 27, 2018: Journal of Pharmacology and Experimental Therapeutics
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
#18
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/29482963/gut-microbiome-composition-in-lean-patients-with-nash-is-associated-with-liver-damage-independent-of-caloric-intake-a-prospective-pilot-study
#19
S M B Duarte, J T Stefano, L Miele, F R Ponziani, M Souza-Basqueira, L S R R Okada, F G de Barros Costa, K Toda, D F C Mazo, E C Sabino, F J Carrilho, A Gasbarrini, C P Oliveira
BACKGROUND AND AIM: The aim of the study was to compare the gut microbiomes from obese and lean patients with or without NASH to outline phenotypic differences. METHODS AND RESULTS: We performed a cross-sectional pilot study comprising biopsy-proven NASH patients grouped according to BMI. Microbiome DNA was extracted from stool samples, and PCR amplification was performed using primers for the V4 region of the 16S rRNA gene. The amplicons were sequenced using the Ion PGM Torrent platform, and data were analyzed using QIIME software...
October 26, 2017: Nutrition, Metabolism, and Cardiovascular Diseases: NMCD
https://www.readbyqxmd.com/read/29466845/duodenal-niemann-pick-c1-like-1-expression-was-negatively-correlated-with-liver-x-receptor-expression-in-nonalcoholic-fatty-liver-disease
#20
Sang Bong Ahn, Dae Won Jun, Kiseok Jang, Byung Hoon Lee, Kye Jung Shin
Background/Aims: Intestinal cholesterol absorption includes intestinal Niemann-Pick C1-like 1 (NPC1L1) and is an important target pathway in nonalcoholic fatty liver disease (NAFLD). We investigated the expression of NPC1L1 and its correlation with liver X receptor (LXR) expression in peripheral mononuclear (PMN) cells in patients with NAFLD. Methods: We evaluated intestinal expression of NPC1L1 in 25 NAFLD patients and 28 healthy controls. We calculated the mRNA expression levels of LXR and farnesoid X receptor (FXR), which are master players of cholesterol metabolism in PMN cells...
February 23, 2018: Korean Journal of Internal Medicine
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