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https://www.readbyqxmd.com/read/28647362/farnesoid-x-receptor-agonist-gw4064-ameliorates-lipopolysaccharide-induced-ileocolitis-through-tlr4-myd88-pathway-related-mitochondrial-dysfunction-in-mice
#1
Hsuan-Miao Liu, Jyh-Fe Liao, Tzung-Yan Lee
Inflammatory bowel disease (IBD) is a complex and relapsing inflammatory condition of the gastro intestinal tract characterized by diarrhea and abdominal pain. Farnesoid X receptor (FXR) plays an important role in enteroprotection and mucosal injury by regulating inflammatory responses and barrier function in the intestinal tract. Here we show the mechanisms of FXR agonist, GW4064, inhibits mucosal injury in ileum caused by lipopolysaccharides (LPS). Ileum injury was induced by intraperitoneal injection of LPS in Wild-type (WT) and FXR knockout (KO) mice...
June 21, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28646179/herbal-medicine-yinchenhaotang-protects-against-%C3%AE-naphthylisothiocyanate-induced-cholestasis-in-rats
#2
Jingyu Yan, Guoxiang Xie, Chungeng Liang, Yiyang Hu, Aihua Zhao, Fengjie Huang, Ping Hu, Ping Liu, Wei Jia, Xiaoning Wang
Cholestasis is a clinical disorder defined as an impairment of bile flow, and that leads to toxic bile acid (BA) accumulation in hepatocytes. Here, we investigated the hepatoprotective effect of Yinchenhaotang (YCHT), a well-known formulae for the treatment of jaundice and liver disorders, against the cholestasis using the α-naphthylisothiocyanate (ANIT)-induced cholestasis in male Wistar rats. ANIT feeding induced significant cholestasis with substantially increased intrahepatic retention of hydrophobic BAs...
June 23, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28629595/a-novel-intestinal-restricted-fxr-agonist
#3
Hong Wang, Zhou Zhao, Jiyu Zhou, Yitong Guo, Guangji Wang, Haiping Hao, Xiaowei Xu
In this study, a new intestinal-restricted FXR agonist named fexaramine-3 (Fex-3) was developed and investigated both in vitro and in vivo. Fex-3 could selectively activate intestinal FXR and promote the expression of BSEP and SHP while suppressing CYP7A1 which is involved in bile acids syntheses better than the reported intestinal-restricted FXR agonist fexaramine (Fex). We demonstrated that Fex-3 targeted on FXR in ileum and has better selectivity than Fex. And the study of utilizing Fex-3 to reduce obesity was undergoing...
June 3, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28619996/farnesoid-x-receptor-and-liver-x-receptor-ligands-initiate-formation-of-coated-platelets
#4
Amanda J Unsworth, Alexander P Bye, Dionne S Tannetta, Michael J R Desborough, Neline Kriek, Tanya Sage, Harriet E Allan, Marilena Crescente, Parveen Yaqoob, Timothy D Warner, Chris I Jones, Jonathan M Gibbins
OBJECTIVES: The liver X receptors (LXRs) and farnesoid X receptor (FXR) have been identified in human platelets. Ligands of these receptors have been shown to have nongenomic inhibitory effects on platelet activation by platelet agonists. This, however, seems contradictory with the platelet hyper-reactivity that is associated with several pathological conditions that are associated with increased circulating levels of molecules that are LXR and FXR ligands, such as hyperlipidemia, type 2 diabetes mellitus, and obesity...
June 15, 2017: Arteriosclerosis, Thrombosis, and Vascular Biology
https://www.readbyqxmd.com/read/28617232/tigeri-modeling-and-visualizing-the-responses-to-perturbation-of-a-transcription-factor-network
#5
Namshik Han, Harry A Noyes, Andy Brass
BACKGROUND: Transcription factor (TF) networks play a key role in controlling the transfer of genetic information from gene to mRNA. Much progress has been made on understanding and reverse-engineering TF network topologies using a range of experimental and theoretical methodologies. Less work has focused on using these models to examine how TF networks respond to changes in the cellular environment. METHODS: In this paper, we have developed a simple, pragmatic methodology, TIGERi (Transcription-factor-activity Illustrator for Global Explanation of Regulatory interaction), to model the response of an inferred TF network to changes in cellular environment...
May 31, 2017: BMC Bioinformatics
https://www.readbyqxmd.com/read/28605664/soy-compared-with-milk-protein-in-a-western-diet-changes-fecal-microbiota-and-decreases-hepatic-steatosis-in-obese-oletf-rats
#6
Matthew R Panasevich, Colin M Schuster, Kathryn E Phillips, Grace M Meers, Sree V Chintapalli, Umesh D Wankhade, Kartik Shankar, Dustie N Butteiger, Elaine S Krul, John P Thyfault, R Scott Rector
Soy protein is effective at preventing hepatic steatosis; however, the mechanisms are poorly understood. We tested the hypothesis that soy vs. dairy protein-based diet would alter microbiota and attenuate hepatic steatosis in hyperphagic Otsuka Long-Evans Tokushima fatty (OLETF) rats. Male OLETF rats were randomized to "Western" diets containing milk protein isolate (MPI), soy protein isolate (SPI) or 50:50 MPI/SPI (MS) (n=9-10/group; 21% kcal protein) for 16 weeks. SPI attenuated (P<.05) fat mass and percent fat by ~10% compared with MS, but not compared with MPI...
May 31, 2017: Journal of Nutritional Biochemistry
https://www.readbyqxmd.com/read/28602676/interactions-between-gut-bacteria-and-bile-in-health-and-disease
#7
REVIEW
Sarah L Long, Cormac G M Gahan, Susan A Joyce
Bile acids are synthesized from cholesterol in the liver and released into the intestine to aid the digestion of dietary lipids. The host enzymes that contribute to bile acid synthesis in the liver and the regulatory pathways that influence the composition of the total bile acid pool in the host have been well established. In addition, the gut microbiota provides unique contributions to the diversity of bile acids in the bile acid pool. Gut microbial enzymes contribute significantly to bile acid metabolism through deconjugation and dehydroxylation reactions to generate unconjugated bile acids and secondary bile acids...
June 21, 2017: Molecular Aspects of Medicine
https://www.readbyqxmd.com/read/28596381/a-dual-agonist-of-farnesoid-x-receptor-fxr-and-the-g-protein-coupled-receptor-tgr5-int-767-slows-down-age-related-kidney-disease-in-mice
#8
Xiaoxin X Wang, Yuhuan Luo, Dong Wang, Luciano Adorini, Mark Pruzanski, Evgenia Dobrinskikh, Moshe Levi
Even in healthy individuals, renal function gradually declines during aging. However, an observed variation in the rate of this decline has raised the possibility of slowing or delaying age-related kidney disease. One of the most successful interventional measures that slows down and delays age-related kidney disease is caloric restriction. We undertook the present studies to search for potential factors that are regulated by caloric restriction and act as caloric restriction mimetics. Based on our prior studies with the bile acid-activated nuclear hormone receptor farnesoid X receptor (FXR) and G protein coupled membrane receptor TGR5 that demonstrated beneficial effects of FXR and TGR5 activation in the kidney, we reasoned that FXR and TGR5 could be excellent candidates...
June 8, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28591793/dynamics-of-bile-acid-profiles-glp-1-and-fgf19-after-laparoscopic-gastric-banding
#9
Veronika Thöni, Alexandra Pfister, Andreas Melmer, Barbara Enrich, Karin Salzmann, Susanne Kaser, Claudia Lamina, Christoph F Ebenbichler, Hubert Hackl, Herbert Tilg, Alexander R Moschen
Context: Increase of bile acids (BAs), fibroblast growth factor 19 (FGF19) and glucagon-like peptide 1 (GLP-1) has been implicated in metabolic improvements after Roux-en-Y gastric bypass (RYGB) and vertical sleeve gastrectomy (VSG), whereas data are still conflicting regarding their role after laparoscopic adjustable gastric banding (LAGB). Objective: To assess fasting BA, FGF19 and GLP-1 concentrations in plasma before and after LAGB and to test for correlations with immuno-metabolic parameters...
June 7, 2017: Journal of Clinical Endocrinology and Metabolism
https://www.readbyqxmd.com/read/28586124/shp-deletion-prevents-hepatic-steatosis-and-when-combined-with-fxr-loss-protects-against-type-2-diabetes
#10
Oludemilade Akinrotimi, Ryan Riessen, Philip VanDuyne, Jung Eun Park, Yoon Kwang Lee, Lee-Jun Wong, Ann M Zavacki, Kristina Schoonjans, Sayeepriyadarshini Anakk
Nuclear receptors Farnesoid X Receptor (FXR) and Small Heterodimer Partner (SHP) are important regulators of bile acid, lipid and glucose homeostasis. Here we show that global Fxr (-/-) Shp(-/-) double knockout (DKO) mice are refractory to weight gain, glucose intolerance and hepatic steatosis when challenged with high-fat diet. DKO mice display an inherently increased capacity to burn fat and suppress de novo hepatic lipid synthesis. Moreover, DKO mice are also very active and that correlates well with the observed increase in Pepck expression, type IA fibers and mitochondrial function in the skeletal muscle...
June 6, 2017: Hepatology: Official Journal of the American Association for the Study of Liver Diseases
https://www.readbyqxmd.com/read/28580281/glucagon-like-peptide-2-promotes-gallbladder-refilling-via-a-tgr5-independent-glp-2r-dependent-pathway
#11
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/28573213/chemoproteomic-profiling-of-bile-acid-interacting-proteins
#12
Shentian Zhuang, Qiang Li, Lirong Cai, Chu Wang, Xiaoguang Lei
Bile acids (BAs) are a family of endogenous metabolites synthesized from cholesterol in liver and modified by microbiota in gut. Being amphipathic molecules, the major function of BAs is to help with dietary lipid digestion. In addition, they also act as signaling molecules to regulate lipid and glucose metabolism as well as gut microbiota composition in the host. Remarkably, recent discoveries of the dedicated receptors for BAs such as FXR and TGR5 have uncovered a number of novel actions of BAs as signaling hormones which play significant roles in both physiological and pathological conditions...
May 24, 2017: ACS Central Science
https://www.readbyqxmd.com/read/28560412/farnesoid-x-receptor-deletion-improves-cardiac-function-structure-and-remodeling-following-myocardial-infarction-in-mice
#13
Jianshu Gao, Xiaoqiang Liu, Bingjian Wang, Haiyan Xu, Qiang Xia, Tianfei Lu, Fang Wang
The farnesoid X receptor (FXR) is implicated in cholesterol and bile acid homeostasis; however, its role following myocardial infarction (MI) has yet to be elucidated. The aim of the present study was to investigate the effects of FXR knockout on left ventricular (LV) remodeling following MI. Coronary arteries of wild type (WT) and FXR‑/‑ mice were permanently occluded to cause MI, and serial echocardiographic and histological tests were conducted. At 4 weeks post‑MI, FXR‑/‑ mice exhibited significantly smaller infarct sizes (34...
July 2017: Molecular Medicine Reports
https://www.readbyqxmd.com/read/28560290/farnesoid-x-receptor-agonist-treatment-alters-bile-acid-metabolism-but%C3%A2-exacerbates-liver-damage-in-a-piglet-model-of-short-bowel%C3%A2-syndrome
#14
Prue M Pereira-Fantini, Susan Lapthorne, Cormac G M Gahan, Susan A Joyce, Jenny Charles, Peter J Fuller, Julie E Bines
BACKGROUND & AIMS: Options for the prevention of short-bowel syndrome-associated liver disease (SBS-ALDs) are limited and often ineffective. The farnesoid X receptor (FXR) is a newly emerging pharmaceutical target and FXR agonists have been shown to ameliorate cholestasis and metabolic disorders. The aim of this study was to assess the efficacy of obeticholic acid (OCA) treatment in preventing SBS-ALDs. METHODS: Piglets underwent 75% small-bowel resection (SBS) or sham surgery (sham) and were assigned to either a daily dose of OCA (2...
July 2017: Cellular and Molecular Gastroenterology and Hepatology
https://www.readbyqxmd.com/read/28553227/srt1720-alleviates-anit-induced-cholestasis-in-a-mouse-model
#15
Linxi Yu, Xiaoxin Liu, Zihang Yuan, Xiaojiaoyang Li, Hang Yang, Ziqiao Yuan, Lixin Sun, Luyong Zhang, Zhengzhou Jiang
Intrahepatic cholestasis is a kind of clinical syndrome along with hepatotoxicity which caused by intrahepatic and systemic accumulations of bile acid. There are several crucial generating factors of the pathogenesis of cholestasis, such as inflammation, dysregulation of bile acid transporters and oxidative stress. SIRT1 is regarded as a class III histone deacetylase (HDAC). According to a set of researches, SIRT1 is one of the most important factors which can regulate the hepatic bile acid metabolism. SRT1720 is a kind of activator of SIRT1 which is 1000 times more potent than resveratrol, and this paper is aimed to study its protective influence on hepatotoxicity and cholestasis induced by alpha-naphthylisothiocyanate (ANIT) in mice...
2017: Frontiers in Pharmacology
https://www.readbyqxmd.com/read/28549616/pectin-penta-oligogalacturonide-reduces-cholesterol-accumulation-by-promoting-bile-acid-biosynthesis-and-excretion-in-high-cholesterol-fed-mice
#16
Ru-Gang Zhu, Yan-Di Sun, Yu-Ting Hou, Jun-Gang Fan, Gang Chen, Tuo-Ping Li
Haw pectin penta-oligogalacturonide (HPPS) has important role in improving cholesterol metabolism and promoting the conversion of cholesterol to bile acids (BA) in mice fed high-cholesterol diet (HCD). However, the mechanism is not clear. This study aims to investigate the effects of HPPS on cholesterol accumulation and the regulation of hepatic BA synthesis and transport in HCD-fed mice. Results showed that HPPS significantly decreased plasma and hepatic TC levels but increased plasma high-density lipoprotein cholesterol (HDL-C) and apolipoprotein A-I (apoA-I) levels, compared to HCD...
June 25, 2017: Chemico-biological Interactions
https://www.readbyqxmd.com/read/28549143/bile-acids-and-tryptophan-metabolism-are-novel-pathways-involved-in-metabolic-abnormalities-in-bpa-exposed-pregnant-mice-and-male-offspring
#17
Martha Susiarjo, Frances Xin, Martha Stefaniak, Clementina Mesaros, Rebecca A Simmons, Marisa S Bartolomei
Increasing evidence has demonstrated that exposure to endocrine disrupting chemicals (EDCs) impacts maternal and fetal health, but the underlying mechanisms are still unclear. We have previously shown that dietary exposure to 10 µg/kg bw/day and 10 mg/kg bw/day bisphenol A (BPA) during pregnancy induced metabolic abnormalities in F1 male offspring and gestational glucose intolerance in F0 pregnant mice. The aim of this study is to elucidate the underlying etiologies of BPA exposure-induced metabolic disease by analyzing male fetal liver metabolome...
May 25, 2017: Endocrinology
https://www.readbyqxmd.com/read/28546081/targeting-nuclear-receptors-for-the-treatment-of-fatty-liver-disease
#18
REVIEW
Naoki Tanaka, Toshifumi Aoyama, Shioko Kimura, Frank J Gonzalez
Ligand-activated nuclear receptors, including peroxisome proliferator-activated receptor alpha (PPARα), pregnane X receptor, and constitutive androstane receptor, were first identified as key regulators of the responses against chemical toxicants. However, numerous studies using mouse disease models and human samples have revealed critical roles for these receptors and others, such as PPARβ/δ, PPARγ, farnesoid X receptor (FXR), and liver X receptor (LXR), in maintaining nutrient/energy homeostasis in part through modulation of the gut-liver-adipose axis...
May 23, 2017: Pharmacology & Therapeutics
https://www.readbyqxmd.com/read/28536529/activation-of-sirt1-fxr-signaling-pathway-attenuates-triptolide-induced-hepatotoxicity-in-rats
#19
Jing Yang, Lixin Sun, Lu Wang, Hozeifa M Hassan, Xuan Wang, Phillip B Hylemon, Tao Wang, Huiping Zhou, Luyong Zhang, Zhenzhou Jiang
Triptolide (TP), a diterpenoid isolated from Tripterygium wilfordii Hook F, has an excellent pharmacological profile of immunosuppression and anti-tumor activities, but its clinical applications are severely restricted due to its severe and cumulative toxicities. The farnesoid X receptor (FXR) is the master bile acid nuclear receptor and plays an important role in maintaining hepatic metabolism homeostasis. Hepatic Sirtuin (Sirt1) is a key regulator of the FXR signaling pathway and hepatic metabolism homeostasis...
2017: Frontiers in Pharmacology
https://www.readbyqxmd.com/read/28535186/fxr-gankyrin-axis-is-involved-in-development-of-pediatric-liver-cancer
#20
Leila Valanejad, Kyle Lewis, Mary Wright, Yanjun Jiang, Amber D'Souza, Rebekah Karns, Rachel Sheridan, Anita Gupta, Kevin Bove, David Witte, James Geller, Gregory Tiao, David L Nelson, Lubov Timchenko, Nikolai Timchenko
The development of hepatoblastoma (HBL) is associated with failure of hepatic stem cells (HSC) to differentiate into hepatocytes. Despite intensive investigations, mechanisms of the failure of HSC to differentiate are not known. We found that oncogene Gankyrin (Gank) is involved in the inhibition of differentiation of HSC via triggering degradation of tumor suppressor proteins (TSPs) Rb, p53, C/EBPα and HNF4α. Our data show that the activation of a repressor of Gank, farnesoid X receptor, FXR, after initiation of liver cancer by Diethylnitrosamine (DEN) prevents the development of liver cancer by inhibiting Gank and rescuing tumor suppressor proteins...
May 23, 2017: Carcinogenesis
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