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https://www.readbyqxmd.com/read/29235094/effects-of-corilagin-on-alleviating-cholestasis-via-fxr-associated-pathways-in-vitro-and-in-vivo
#1
Fan Yang, Yao Wang, Gang Li, Juan Xue, Zhi-Lin Chen, Feng Jin, Lei Luo, Xuan Zhou, Qian Ma, Xin Cai, Hua-Rong Li, Lei Zhao
BACKGROUND AND PURPOSE: This aim of this study was to investigate the effects of corilagin on alleviating intrahepatic cholestasis by regulating liver FXR (farnesoid X receptor)-associated pathways in vitro and in vivo. EXPERIMENTAL APPROACH: Cellular and animal models were treated with different concentrations of corilagin. In the cellular experiments, FXR expression was up-regulated by either lentiviral transduction or GW4064 treatment and down-regulated by either siRNA technology or treatment with guggulsterones...
December 12, 2017: British Journal of Pharmacology
https://www.readbyqxmd.com/read/29235014/increased-bile-acid-signals-after-duodenal-jejunal-bypass-improve-non-alcoholic-steatohepatitis-nash-in-a-rodent-model-of-diet-induced-nash
#2
Takahiro Tsuchiya, Takeshi Naitoh, Munenori Nagao, Naoki Tanaka, Kazuhiro Watanabe, Hirofumi Imoto, Tomohiro Miyachi, Fuyuhiko Motoi, Michiaki Unno
BACKGROUND: The increasing incidence of non-alcoholic steatohepatitis (NASH) has resulted in it becoming a common cause of liver-related mortality; however, no efficient treatment has been established. It has been reported that bariatric surgery improves metabolic comorbidities, such as diabetes mellitus and NASH. Although the mechanism is unclear, it is thought that the changes in bile acid (BA) signaling via its nuclear receptor, farnesoid X receptor (FXR), produce various metabolic effects...
December 12, 2017: Obesity Surgery
https://www.readbyqxmd.com/read/29233934/chronic-infusion-of-taurolithocholate-into-the-brain-increases-fat-oxidation-in-mice
#3
Hannah M Eggink, Lauren L Tambyrajah, Rosa van den Berg, Isabel Mol, Jose K van den Heuvel, Martijn Koehorst, Albert K Groen, Anita Boelen, Andries Kalsbeek, Johannes A Romijn, Patrick C N Rensen, Sander Kooijman, Maarten R Soeters
Bile acids can function in the postprandial state as circulating signaling molecules in the regulation of glucose and lipid metabolism via the transmembrane receptor TGR5 and nuclear receptor FXR. Both receptors are present in the central nervous system, but their function in the brain is unclear. Therefore, we investigated the effects of intracerebroventricular (icv) administration of taurolithocholate (tLCA), a strong TGR5 agonist, and GW4064, a synthetic FXR agonist, on energy metabolism. We determined the effects of chronic icv infusion of tLCA, GW4064, or vehicle on energy expenditure, body weight and composition as well as tissue specific fatty acid uptake in mice equipped with osmotic minipumps...
December 12, 2017: Journal of Endocrinology
https://www.readbyqxmd.com/read/29228599/chicken-bile-powder-protects-against-%C3%AE-naphthylisothiocyanate-induced-cholestatic-liver-injury-in-mice
#4
Yi-Fei Li, Jia-Sheng Wu, Yuan-Yuan Li, Yan Dai, Min Zheng, Jia-Kai Zeng, Guo-Feng Wang, Tian-Ming Wang, Wen-Kai Li, Xue-Yan Zhang, Ming Gu, Cheng Huang, Li Yang, Zheng-Tao Wang, Yue-Ming Ma
This study explored the effects of chicken bile powder (CBP), a 2000-year-old Chinese medicine, on α-naphthyl isothiocyanate (ANIT)-induced intrahepatic cholestasis in mice. CBP treatment for 14 days significantly ameliorated ANIT-induced changes in serum alanine aminotransferase, aspartate aminotransferase, bile acids, bilirubin, γ-glutamyl transpeptidase, alkaline phosphatase, and liver tissue morphology. Serum metabolomics showed changes in 24 metabolites in ANIT-exposed mice; 16 of these metabolites were reversed by CBP treatment via two main pathways (bile acid biosynthesis and arachidonic acid metabolism)...
November 14, 2017: Oncotarget
https://www.readbyqxmd.com/read/29226620/comparative-potency-of-obeticholic-acid-and-natural-bile-acids-on-fxr-in-hepatic-and-intestinal-in%C3%A2-vitro-cell-models
#5
Yuanyuan Zhang, Carl LaCerte, Sanjay Kansra, Jonathan P Jackson, Kenneth R Brouwer, Jeffrey E Edwards
Obeticholic acid (OCA) is a semisynthetic farnesoid X receptor (FXR) agonist, an analogue of chenodeoxycholic acid (CDCA) which is indicated for the treatment of primary biliary cholangitis (PBC) in combination with ursodeoxycholic acid (UDCA). OCA efficiently inhibits bile acid synthesis and promotes bile acid efflux via activating FXR-mediated mechanisms in a physiologically relevant in vitro cell system, Sandwich-cultured Transporter Certified ™ human primary hepatocytes (SCHH). The study herein evaluated the effects of UDCA alone or in combination with OCA in SCHH...
December 2017: Pharmacology Research & Perspectives
https://www.readbyqxmd.com/read/29222744/activation-of-intestinal-gr-fxr-and-ppar%C3%AE-ugt-signaling-exacerbates-ibuprofen-induced-enteropathy-in-mice
#6
Zhiqiang Lu, Yuanfu Lu, Xue Wang, Fangyu Wang, Youcai Zhang
Nonsteroidal anti-inflammatory drugs (NSAIDs)-induced small intestinal injury (enteropathy) occurs in about two-thirds of regular NSAID users. To date, there is no proven-effective treatment for NSAID enteropathy, and its underlying mechanism remains obscure. The present study showed that glucocorticoids are an important determinant of NSAID enteropathy. High dose dexamethasone (DEX, 75 mg/kg) markedly exacerbated the acute toxicity of ibuprofen (IBU, 200 mg/kg) in the small intestine of mice, which was not due to the pregnane-X-receptor pathway...
December 8, 2017: Archives of Toxicology
https://www.readbyqxmd.com/read/29222421/the-transcriptomic-signature-of-disease-development-and-progression-of-nonalcoholic-fatty-liver-disease
#7
Sophie Cazanave, Alexei Podtelezhnikov, Kristian Jensen, Mulugeta Seneshaw, Divya P Kumar, Hae-Ki Min, Prasanna K Santhekadur, Bubu Banini, Adolfo Gabriele Mauro, Abdul M Oseini, Robert Vincent, Keith Q Tanis, Andrea L Webber, Liangsu Wang, Pierre Bedossa, Faridoddin Mirshahi, Arun J Sanyal
A longitudinal molecular model of the development and progression of nonalcoholic fatty liver disease (NAFLD) over time is lacking. We have recently validated a high fat/sugar water-induced animal (an isogenic strain of C57BL/6 J:129S1/SvImJ mice) model of NAFLD that closely mimics most aspects of human disease. The hepatic transcriptome of such mice with fatty liver (8 weeks), steatohepatitis with early fibrosis (16-24 weeks) and advanced fibrosis (52 weeks) after initiation of the diet was evaluated and compared to mice on chow diet...
December 8, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29216638/microrna-122-inhibits-lipid-droplet-formation-and-hepatic-triglyceride-accumulation-via-yin-yang-1
#8
Guo-Yi Wu, Chen Rui, Ji-Qiao Chen, Eiketsu Sho, Shan-Shan Zhan, Xian-Wen Yuan, Yi-Tao Ding
BACKGROUND/AIMS: An increase in intracellular lipid droplet formation and hepatic triglyceride (TG) content usually results in nonalcoholic fatty liver disease. However, the mechanisms underlying the regulation of hepatic TG homeostasis remain unclear. METHODS: Oil red O staining and TG measurement were performed to determine the lipid content. miRNA expression was evaluated by quantitative PCR. A luciferase assay was performed to validate the regulation of Yin Yang 1 (YY1) by microRNA (miR)-122...
December 6, 2017: Cellular Physiology and Biochemistry
https://www.readbyqxmd.com/read/29213261/antibiotic-induced-alterations-in-gut-microbiota-are-associated-with-changes-in-glucose-metabolism-in-healthy-mice
#9
Richard R Rodrigues, Renee L Greer, Xiaoxi Dong, Karen N DSouza, Manoj Gurung, Jia Y Wu, Andrey Morgun, Natalia Shulzhenko
The gut microbiome plays an important role in health and disease. Antibiotics are known to alter gut microbiota, yet their effects on glucose tolerance in lean, normoglycemic mice have not been widely investigated. In this study, we aimed to explore mechanisms by which treatment of lean mice with antibiotics (ampicillin, metronidazole, neomycin, vancomycin, or their cocktail) influences the microbiome and glucose metabolism. Specifically, we sought to: (i) study the effects on body weight, fasting glucose, glucose tolerance, and fasting insulin, (ii) examine the changes in expression of key genes of the bile acid and glucose metabolic pathways in the liver and ileum, (iii) identify the shifts in the cecal microbiota, and (iv) infer interactions between gene expression, microbiome, and the metabolic parameters...
2017: Frontiers in Microbiology
https://www.readbyqxmd.com/read/29204945/d3r-grand-challenge-2-blind-prediction-of-protein-ligand-poses-affinity-rankings-and-relative-binding-free-energies
#10
Zied Gaieb, Shuai Liu, Symon Gathiaka, Michael Chiu, Huanwang Yang, Chenghua Shao, Victoria A Feher, W Patrick Walters, Bernd Kuhn, Markus G Rudolph, Stephen K Burley, Michael K Gilson, Rommie E Amaro
The Drug Design Data Resource (D3R) ran Grand Challenge 2 (GC2) from September 2016 through February 2017. This challenge was based on a dataset of structures and affinities for the nuclear receptor farnesoid X receptor (FXR), contributed by F. Hoffmann-La Roche. The dataset contained 102 IC50 values, spanning six orders of magnitude, and 36 high-resolution co-crystal structures with representatives of four major ligand classes. Strong global participation was evident, with 49 participants submitting 262 prediction submission packages in total...
December 4, 2017: Journal of Computer-aided Molecular Design
https://www.readbyqxmd.com/read/29202514/glycyrrhetic-acid-derivative-ty501-protects-against-lithocholic-acid-induced-cholestasis
#11
Xuemin Zheng, Shichao Zhu, Zhixing Zhou, Wei Liu, Weiren Xu
The aim of the study is to investigate the protective effects of TY501 against LCA-induced cholestasis in mice and to explore the potential mechanisms. It was demonstrated that TY501(5, 15 or 45 mg/kg, i.g.) can markedly reduced the level of ALT, AST and ALP which increased by LCA treatment. Meanwhile, TY501 also lowered total bile acids, total bilirubin and total cholesterol levels in serum. Furthermore, TY501 can protect HepG2 cell cultures from LCA-induced cytotoxicity. RT-PCR and Western Blot analysis showed that TY501 recovered the expression of BSEP, MRP2 and NTCP which were down-regulated by LCA...
December 4, 2017: Drug Research
https://www.readbyqxmd.com/read/29198707/impaired-vagus-function-in-rats-suppresses-bile-acid-synthesis-in-the-liver-by-disrupting-tight-junctions-and-activating-fxr-fgf15-signaling-in-the-intestine
#12
Fangyu Wang, Zhiqiang Lu, Xue Wang, Youcai Zhang
Bile acids (BAs) circulate between the liver and intestine, and regulate the homeostasis of glucose, lipid, and energy. Recent studies demonstrated an essential role of BAs in neurological diseases, suggesting an interaction between BAs and the nervous system. In the present study, we showed that impaired vagus function in rats induced by vagotomy resulted in an increase in bile flow without causing liver injury. The concentrations of unconjugated and glycine-conjugated BAs were increased in both serum and bile of rats after vagotomy, which was due to impaired tight junctions and thus increased passive absorption of BAs in the intestine...
November 30, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/29188025/recent-advances-in-understanding-bile-acid-homeostasis
#13
REVIEW
John Yl Chiang
Bile acids are derived from cholesterol to facilitate intestinal nutrient absorption and biliary secretion of cholesterol. Recent studies have identified bile acids as signaling molecules that activate nuclear farnesoid X receptor (FXR) and membrane G protein-coupled bile acid receptor-1 (Gpbar-1, also known as TGR5) to maintain metabolic homeostasis and protect liver and other tissues and cells from bile acid toxicity. Bile acid homeostasis is regulated by a complex mechanism of feedback and feedforward regulation that is not completely understood...
2017: F1000Research
https://www.readbyqxmd.com/read/29177335/molecular-actions-of-hypocholesterolaemic-compounds-from-edible-mushrooms
#14
REVIEW
Alicia Gil-Ramírez, Diego Morales, Cristina Soler-Rivas
Cholesterol levels are strictly regulated to maintain its homeostasis; therefore, if it is not absorbed with the diet, the cholesterol biosynthetic pathway is enhanced and vice versa. Nowadays, the commonly prescribed therapeutic treatments for hypocholesterolemic patients are targeted toward the reduction of both cholesterol intestinal absorption and/or its endogenous biosynthesis. But, when hypercholesterolemia is still moderate the consumption of food products with cholesterol-lowering capacities is more desirable than using drugs...
November 27, 2017: Food & Function
https://www.readbyqxmd.com/read/29175670/apoe-is-a-major-determinant-of-hepatic-bile-acid-homeostasis-in-mice
#15
Sandra von Hardenberg, Carsten Gnewuch, Gerd Schmitz, Jürgen Borlak
Apolipoprotein E (ApoE) plays a central role in lipid transport and cholesterol metabolism, with surplus cholesterol being removed from the liver through bile acid (BA) synthesis. Furthermore, BAs are of critical importance in fat absorption by forming intestinal lipid-bile salt mixed micelles. To define ApoE's role in BA homeostasis, the metabolism of cholesterol and BA was investigated in liver tissue and gallbladder bile of ApoE-deficient mice given a chow or high-cholesterol/high-fat diet (HCHF) diet for 6 months...
September 28, 2017: Journal of Nutritional Biochemistry
https://www.readbyqxmd.com/read/29175453/activation-of-ppar%C3%AE-decreases-bile-acids-in-livers-of-female-mice-while-maintaining-bile-flow-and-biliary-bile-acid-excretion
#16
Youcai Zhang, Andrew J Lickteig, Iván L Csanaky, Curtis D Klaassen
Fibrates are hypolipidemic drugs that act as activators of peroxisome proliferator-activated receptor α (PPARα). In both humans and rodents, females were reported to be less responsive to fibrates than males. Previous studies on fibrates and PPARα usually involved male mice, but little has been done in females. The present study aimed to provide the first comprehensive analysis of the effects of clofibrate (CLOF) and PPARα on bile acid (BA) homeostasis in female mice. Study in WT male mice showed that a 4-day CLOF treatment increased liver weight, bile flow, and biliary BA excretion, but decreased total BAs in both serum and liver...
November 22, 2017: Toxicology and Applied Pharmacology
https://www.readbyqxmd.com/read/29174575/obeticholic-acid-protects-mice-against-lipopolysaccharide-induced-liver-injury-and-inflammation
#17
Xi Xiong, Yuqian Ren, Yun Cui, Rui Li, Chunxia Wang, Yucai Zhang
BACKGROUND: Cholestasis, as a main manifestation, induces liver injury during sepsis. The farnesoid X receptor (FXR) plays an important role in regulating bile acid homeostasis. Whether FXR activation by its agonist obeticholic acid (OCA) is contributed to improve sepsis-induced liver injury remains unknown. OBJECTIVE: The aim of the present study was to investigate the effect of OCA on lipopolysaccharide (LPS)-induced acute liver injury in mice. RESULTS: 8-week old male C57BL/6J mice were randomly divided into control group, LPS group, oral OCA group and LPS plus oral OCA (LPS + OCA) group...
November 21, 2017: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
https://www.readbyqxmd.com/read/29173647/diet-induced-obesity-and-weight-loss-alter-bile-acid-concentrations-and-bile-acid-sensitive-gene-expression-in-insulin-target-tissues-of-c57bl-6j-mice
#18
Michael R La Frano, Angelina Hernandez-Carretero, Natalie Weber, Kamil Borkowski, Theresa L Pedersen, Olivia Osborn, John W Newman
Bile acids (BAs) influence the metabolism of glucose, lipids, and energy expenditure. We hypothesized that BA concentrations and related gene expression would be altered in lean (low-fat diet fed; LFD) vs diet-induced obese (high-fat diet fed; HFD) groups of mice and that some detected changes would remain after weight loss in an HFD group switched to the LFD (SW). Taurine conjugates dominated the bile acid composition of the liver, epididymal white adipose tissue (eWAT), and hypothalamus, with the latter having lower levels (~95%, ~95%, and ~80%, respectively; P<...
October 2017: Nutrition Research
https://www.readbyqxmd.com/read/29163019/bile-acid-signaling-pathways-from-the-enterohepatic-circulation-to-the-central-nervous-system
#19
REVIEW
Kim L Mertens, Andries Kalsbeek, Maarten R Soeters, Hannah M Eggink
Bile acids are best known as detergents involved in the digestion of lipids. In addition, new data in the last decade have shown that bile acids also function as gut hormones capable of influencing metabolic processes via receptors such as FXR (farnesoid X receptor) and TGR5 (Takeda G protein-coupled receptor 5). These effects of bile acids are not restricted to the gastrointestinal tract, but can affect different tissues throughout the organism. It is still unclear whether these effects also involve signaling of bile acids to the central nervous system (CNS)...
2017: Frontiers in Neuroscience
https://www.readbyqxmd.com/read/29162643/identification-of-an-oleanane-type-triterpene-hedragonic-acid-as-a-novel-farnesoid-x-receptor-ligand-with-liver-protective-effects-and-anti-inflammatory-activity
#20
Yi Lu, Weili Zheng, Shengchen Lin, Fusheng Guo, Yanlin Zhu, Yijuan Wei, Xi Liu, Shikai Jin, Lihua Jin, Yong Li
Farnesoid X receptor (FXR) and G-protein-coupled BA receptor 1 (GPBAR1) are two important bile acid (BA) receptors. As a non-BAs drug template for GPBAR1, none of the natural oleanane-type triterpene has been reported as FXR ligands, despite that FXR and GPBAR1 have similar binding pockets for BAs. Here, we report the natural triterpene hedragonic acid that has been isolated from the stem and root of Celastrus orbiculatus Thunb. (COT) as an effective agonist for FXR. Both biochemical AlphaScreen and cell-based reporter assays showed that hedragonic acid regulated the transcriptional activity of FXR...
November 21, 2017: Molecular Pharmacology
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