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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/28756207/pregnane-x-receptor-pxr-deficiency-improves-high-fat-diet-induced-obesity-via-induction-of-fibroblast-growth-factor-15-fgf15-expression
#2
Li-Yang Zhao, Jia-Yi Xu, Zhe Shi, Neal A Englert, Shu-Yun Zhang
Obesity has become a significant global health problem, and is a high risk factor for a variety of metabolic diseases. Fibroblast growth factor (FGF) 15 plays an important role in the regulation of metabolism. Xenobiotic-sensing nuclear receptors pregnane X receptor (PXR/NR1I2) and constitutive androstane receptor (CAR/NR1I3) play important roles in xenobiotic detoxification and metabolism, and also are involved in the regulation of energy metabolism. However, the effects that PXR and CAR have on the regulation of FGF15 are unknown...
July 26, 2017: Biochemical Pharmacology
https://www.readbyqxmd.com/read/28754826/osteopontin-regulates-the-cross-talk-between-phosphatidylcholine-and-cholesterol-metabolism-in-mouse-liver
#3
Maitane Nuñez-Garcia, Beatriz Gomez-Santos, Xabier Buque, Juan L Garcia-Rodriguez, Marta R Romero, Jose Jg Marin, Beatriz Arteta, Carmelo Garcia-Monzon, Luis Castaño, Wingkin Syn, Olatz Fresnedo, Patricia Aspichueta
Osteopontin (OPN) is involved in different liver pathologies, in which a metabolic dysregulation is a hallmark. Here we investigated whether OPN could alter liver, and more specifically hepatocyte, lipid metabolism and the mechanism involved. In mice, lack of OPN enhances CYP7A1 levels and promotes loss of phosphatidylcholine (PC) content in liver; in vivo treatment with recombinant (r)OPN causes opposite effects. rOPN directly decreases CYP7A1 levels through activation of the FAK-AKT signaling in hepatocytes...
July 28, 2017: Journal of Lipid Research
https://www.readbyqxmd.com/read/28751722/hepatocyte-specific-timp3-expression-prevents-diet-dependent-fatty-liver-disease-and-hepatocellular-carcinoma
#4
Viviana Casagrande, Alessandro Mauriello, Simone Bischetti, Maria Mavilio, Massimo Federici, Rossella Menghini
Non-alcoholic fatty liver disease (NAFLD) encompasses a broad spectrum of conditions, ranging from non-progressive bland steatosis to hepatocarcinoma. Tissue inhibitor of metalloproteinase 3 (Timp3) has a role in the pathogenesis of fatty liver disease associated with obesity and is silenced during metabolic disorders and liver cancer. We generated an hepatocyte-specific TIMP3 'gain-of-function' mouse model under the control of the Albumin promoter (AlbT3) and investigated its effects during high-fat diet (HFD)...
July 27, 2017: Scientific Reports
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
#5
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/28725001/2-3-7-8-tetrachlorodibenzo-p-dioxin-tcdd-elicited-effects-on-bile-acid-homeostasis-alterations-in-biosynthesis-enterohepatic-circulation-and-microbial-metabolism
#6
Kelly A Fader, Rance Nault, Chen Zhang, Kazuyoshi Kumagai, Jack R Harkema, Timothy R Zacharewski
2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is a persistent environmental contaminant which elicits hepatotoxicity through activation of the aryl hydrocarbon receptor (AhR). Male C57BL/6 mice orally gavaged with TCDD (0.01-30 µg/kg) every 4 days for 28 days exhibited bile duct proliferation and pericholangitis. Mass spectrometry analysis detected a 4.6-fold increase in total hepatic bile acid levels, despite the coordinated repression of genes involved in cholesterol and primary bile acid biosynthesis including Cyp7a1...
July 19, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28711947/repression-of-intestinal-transporters-and-fxr-fgf15-signaling-explains-bile-acids-dysregulation-in-experimental-colitis-associated-colon-cancer
#7
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/28706181/effects-of-an-enriched-extract-of-paeoniflorin-a-monoterpene-glycoside-used-in-chinese-herbal-medicine-on-cholesterol-metabolism-in-a-hyperlipidemic-rat-model
#8
Huiming Hu, Qiaoqiao Zhu, Jie Su, Yajun Wu, Yanchen Zhu, Yin Wang, Hui Fang, Minxia Pang, Bo Li, Suhong Chen, Guiyuan Lv
BACKGROUND Paeoniflorin is a monoterpene glycoside extracted from the roots of Paeonia lactiflora and is used in Chinese herbal medicine to treat hyperlipidemia. The aim of this study was to evaluate the effects of an enriched extract of paeoniflorin on cholesterol levels, hemodynamics, and oxidative stress in a hyperlipidemic rat model. MATERIAL AND METHODS Male Sprague-Dawley rats were fed high-cholesterol diets and treated with three different doses of paeoniflorin for 12 weeks. The effects of paeoniflorin treatment were assessed on cholesterol levels, cholesterol metabolism, red blood cell vascular flow using hemorheology, antioxidant enzymes, and expression of the rate-limiting enzyme in the mevalonate pathway, 3-hydroxy-3-methylglutharyl-coenzyme A reductase (HMG-CoAR)...
July 14, 2017: Medical Science Monitor: International Medical Journal of Experimental and Clinical Research
https://www.readbyqxmd.com/read/28695746/improvement-of-hepatogenic-differentiation-of-ips-cells-on-an-aligned-polyethersulfone-compared-to-random-nanofibers
#9
Maryam Mahmoodinia Maymand, Hamid Reza Soleimanpour-Lichaei, Abdolreza Ardeshirylajimi, Masoud Soleimani, Seyed Ehsan Enderami, Shahrzad Nojehdehi, Farkhondeh Behjati, Maryam Kabir Salmani
The application of stem cells holds great promises in cell and tissue transplants. This study was designed to compare the hepatogenic differentiation of iPSCs on aligned PES/COL versus random. Aligned and random PES/COL nanofibrus scaffolds were fabricated by electrospining and their surface modified through plasma treatment and collagen coating. The scaffolds were characterized using scanning electron microscopy (SEM) and ATR-FTIR. Morphology and biochemical activities of the differentiated hepatocyte-like cells (HLCs) were examined after 5 and 20 days of differentiation...
July 11, 2017: Artificial Cells, Nanomedicine, and Biotechnology
https://www.readbyqxmd.com/read/28667746/integrated-gut-liver-microphysiological-systems-elucidates-inflammatory-inter-tissue-crosstalk
#10
Wen L K Chen, Collin Edington, Emily Suter, Jiajie Yu, Jeremy J Velazquez, Jason G Velazquez, Michael Shockley, Emma M Large, Raman Venkataramanan, David J Hughes, Cynthia L Stokes, David L Trumper, Rebecca L Carrier, Murat Cirit, Linda G Griffith, Douglas A Lauffenburger
A capability for analyzing complex cellular communication among tissues is important in drug discovery and development, and in vitro technologies for doing so are required for human applications. A prominent instance is communication between the gut and the liver, whereby perturbations of one tissue can influence behavior of the other. Here, we present a study on human gut-liver tissue interactions under normal and inflammatory contexts, via an integrative multi-organ platform comprising human liver (hepatocytes and Kupffer cells), and intestinal (enterocytes, goblet cells, and dendritic cells) models...
July 1, 2017: Biotechnology and Bioengineering
https://www.readbyqxmd.com/read/28645914/bile-salt-homeostasis-in-normal-and-bsep-gene-knockout-rats-with-single-and-repeated-doses-of-troglitazone
#11
Yaofeng Cheng, Shenjue Chen, Chris Freeden, Weiqi Chen, Yueping Zhang, Pamela Abraham, David M Nelson, W Griffith Humphreys, Jinping Gan, Yurong Lai
The interference of bile acid secretion through bile salt export pump (BSEP) inhibition is one of the mechanisms for troglitazone (TGZ)-induced hepatotoxicity. Here, we investigated the impact of single or repeated oral doses of TGZ (200 mg/kg/day, 7 days) on bile acid homoeostasis in wild-type (WT) and Bsep knockout (KO) rats. Following oral doses, plasma exposures of TGZ were not different between WT and KO rats, and were similar on day 1 and day 7. However, plasma exposures of the major metabolite, troglitazone sulfate (TS), in KO rats were 7...
September 2017: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/28639266/bakuchiol-contributes-to-the-hepatotoxicity-of-psoralea-corylifolia-in-rats
#12
Zhi-Jian Li, Abudumijiti Abulizi, Guo-Lin Zhao, Tao Wang, Fan Zhou, Zhen-Zhou Jiang, Silafu Aibai, Lu-Yong Zhang
Psoralea corylifolia L. (Fructus Psoraleae) is widely used in Asia, but there are concerns about hepatotoxicity caused by constituents such as psoralens and bakukiol. Bakuchiol (BAK) has antiinflammatory, antipyretic, antibacterial antiviral, anticancer, and estrogenic activity but appears to be hepatotoxic in in vitro tests. This study investigated the hepatotoxicity in vivo in rats. Using intragastrically administered bakuchiol at doses of 52.5 and 262.5 mg/kg for 6 weeks. Bodyweight, relative liver weight, biochemical indicators, histopathology, mRNA expression of CYP7A1, HMG-CoA reductase, BSEP, PPARα, SREBP-2, and MRP3 were measured...
August 2017: Phytotherapy Research: PTR
https://www.readbyqxmd.com/read/28629595/a-novel-intestinal-restricted-fxr-agonist
#13
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...
August 1, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28623919/effects-of-karela-bitter-melon-momordica-charantia-on-genes-of-lipids-and-carbohydrates-metabolism-in-experimental-hypercholesterolemia-biochemical-molecular-and-histopathological-study
#14
Dalia Yossri Saad, Mohamed Mohamed Soliman, Ahmed A Baiomy, Magdy Hassan Yassin, Hanan Basiouni El-Sawy
BACKGROUND: Hypercholesterolemia is a serious diseases associated with type-2 diabetes, atherosclerosis, cardiovascular disorders and liver diseases. Humans seek for safe herbal medication such as karela (Momordica charantia/bitter melon) to treat such disorders to avoid side effect of pharmacotherapies widely used. METHODS: Forty male Wistar rats were divided into four equal groups; control group with free access to food and water, cholesterol administered group (40 mg/kg BW orally); karela administered group (5 g /kg BW orally) and mixture of cholesterol and karela...
June 17, 2017: BMC Complementary and Alternative Medicine
https://www.readbyqxmd.com/read/28576870/role-of-mir-383-and-mir-146b-in-different-propensities-to-obesity-in-male-mice
#15
Shu-Fang Xia, Xiao-Mei Duan, Xiang-Rong Cheng, Li-Mei Chen, Yan-Jun Kang, Peng Wang, Xue Tang, Yong-Hui Shi, Guowei Le
The study was designed to investigate the possible mechanisms of hepatic microRNAs (miRs) in regulating local thyroid hormone (TH) action and ultimately different propensities to high-fat diet (HFD) induced obesity. When obesity-prone (OP) and obesity-resistant (OR) mice were fed high-fat diet for 7 weeks, OP mice showed apparent hepatic steatosis, with significantly higher body weight and lower hepatic thyroid hormone receptor b (TRb) expression and type 1 deiodinase (DIO1) activity than OR mice. Next-generation sequencing technology revealed that 13 miRs in liver were dysregulated between the two phenotypes, of which 8 miRs were predicted to target on Dio1 or TRb...
June 2, 2017: Journal of Endocrinology
https://www.readbyqxmd.com/read/28570655/circulating-fgf19-closely-correlates-with-bile-acid-synthesis-and-cholestasis-in-patients-with-primary-biliary-cirrhosis
#16
Zhanyi Li, Bingliang Lin, Guoli Lin, Yuankai Wu, Yusheng Jie, Xiangyong Li, Brian Ko, Yutian Chong, Jian Luo
BACKGROUND AND AIM: Bile acid (BA) synthesis in the liver is regulated by Fibroblast Growth Factor 19 (FGF19) secreted from the ileum as an enterohepatic feedback mechanism. Although FGF19 mRNA is absent in normal liver, FGF19 gene expression was reported to increase in response to both extrahepatic and intrahepatic cholestasis. The impact of upregulated FGF19 expression on BA synthesis is unclear and the overall role of circulating FGF19 and BA synthesis under cholestatic conditions needs to be further investigated...
2017: PloS One
https://www.readbyqxmd.com/read/28549656/glycyrrhizin-and-glycyrrhetinic-acid-inhibits-alpha-naphthyl-isothiocyanate-induced-liver-injury-and-bile-acid-cycle-disruption
#17
Haina Wang, Zhong-Ze Fang, Ran Meng, Yun-Feng Cao, Naoki Tanaka, Kristopher W Krausz, Frank J Gonzalez
Alpha-naphthyl isothiocyanate (ANIT) is a common hepatotoxicant experimentally used to reproduce the pathologies of drug-induced liver injury in humans, but the mechanism of its toxicity remains unclear. To determine the metabolic alterations following ANIT exposure, metabolomic analyses was performed by use of liquid chromatography-mass spectrometry. Partial least squares discriminant analysis (PLS-DA) of liver, serum, bile, ileum, and cecum of vehicle- and ANIT-treated mice revealed significant alterations of individual bile acids, including increased tauroursodeoxycholic acid, taurohydrodeoxycholic acid, taurochenodeoxycholic acid, and taurodeoxycholic acid, and decreased ω-, β- and tauro-α/β- murideoxycholic acid, cholic acid, and taurocholic acid in the ANIT-treated groups...
May 24, 2017: Toxicology
https://www.readbyqxmd.com/read/28549616/pectin-penta-oligogalacturonide-reduces-cholesterol-accumulation-by-promoting-bile-acid-biosynthesis-and-excretion-in-high-cholesterol-fed-mice
#18
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/28549240/dietary-salecan-reverts-partially-the-metabolic-gene-expressions-and-nmr-based-metabolomic-profiles-from-high-fat-diet-induced-obese-rats
#19
Qi Sun, Minghui Li, Xiao Yang, Xi Xu, Junsong Wang, Jianfa Zhang
Previous studies suggest that dietary salecan (a water-soluble β-glucan) effectively reduces high-fat-diet-induced adiposity through disturbing bile-acid-promoted emulsification in mice. However, the effects of salecan on metabolic genes and metabolites involved in lipid accumulation are mostly unknown. Here, we confirmed that dietary 3% and 6% salecan for 4 weeks markedly decreased fat accumulation in liver and adipose tissue in high-fat-diet rats, displaying a decrease in mRNA levels of SREBP1-C, FAS, SCD1 and ACC1 involved in de novo lipogenesis and a reduction of levels of GPAT1, DGAT1 and DGAT2 related to triglyceride synthesis...
May 5, 2017: Journal of Nutritional Biochemistry
https://www.readbyqxmd.com/read/28536529/activation-of-sirt1-fxr-signaling-pathway-attenuates-triptolide-induced-hepatotoxicity-in-rats
#20
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
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