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| 1 | Metabolic and hepatic effects of liraglutide,obeticholic acid and elafibranor in diet-induced obese mouse models of biopsy-confirmed nonalcoholic steatohepatitis显示文摘AIM To evaluate the pharmacodynamics of compounds in clinical development for nonalcoholic steatohepatitis(NASH) in obese mouse models of biopsy-confirmedNASH.METHODS Male wild-type C57 BL/6 J mice(DIO-NASH) and Lep^(ob/ob)(ob/ob-NASH) mice were fed a diet high in trans-fat(40%), fructose(20%) and cholesterol(2%) for 30 and 21 wk, respectively. Prior to treatment, all mice underwent liver biopsy for confirmation and stratification of liver steatosis and fibrosis, using the nonalcoholic fatty liver disease activity score(NAS) and fibrosis staging system. The mice were kept on the diet and received vehicle, liraglutide(0.2 mg/kg, SC, BID), obeticholic acid(OCA, 30 mg/kg PO, QD), or elafibranor(30 mg/kg PO, QD) for eight weeks. Within-subject comparisons were performed on changes in steatosis, inflammation, ballooning degeneration, and fibrosis scores. In addition, compound effects were evaluated by quantitative liver histology, including percent fractional area of liver fat, galectin-3, and collagen 1 a1.RESULTS Liraglutide and elafibranor, but not OCA, reduced body weight in both models. Liraglutide improved steatosis scores in DIO-NASH mice only. Elafibranor and OCA reduced histopathological scores of hepatic steatosis and inflammation in both models, but only elafibranor reduced fibrosis severity. Liraglutide and OCA reduced total liver fat, collagen 1 a1, and galectin-3 content, driven by significant reductions in liver weight. The individual drug effects on NASH histological endpoints were supported by global gene expression(RNA sequencing) and liver lipid biochemistry.CONCLUSION DIO-NASH and ob/ob-NASH mouse models show distinct treatment effects of liraglutide, OCA, and elafibranor, being in general agreement with corresponding findings in clinical trials for NASH. The present data therefore further supports the clinical translatability and utility of DIO-NASH and ob/ob-NASH mouse models of NASH for probing the therapeutic efficacy of compounds in preclinical drug development for NASH. | Kirstine S Tolbol Maria NB Kristiansen Henrik H Hansen Sanne S Veidal Kristoffer TG Rigbolt Matthew P Gillum Jacob Jelsing Niels Vrang Michael Feigh | 2018 | World Journal of Gastroenterology2018，24，2： | 5 |
| 2 | Tumorigenesissuppressor Pdcd4 dow n-regulates mitogen-activated pro-tein kinase 1 expression to suppress colon carcinoma cellinvasion显示文摘 | Yang H S Matthews C P Clair T | 2006 | Mol Cell Biol2006，26，4： | 1 |
| 3 | Evaluation of the biocompatibility of a chitosan scaffold in mice显示文摘 | vander Vord P J Matthew H W DeSilva S P et aI | 2002 | Biomed Mater Res2002，59，3： | 1 |
| 4 | Adaptation of HIV-1to human leukocyte antigen class I显示文摘 | Kawashima Y Pfafferott K Frater J Matthews P Payne R Addo M Gatanaga H Fujiwara M Hachiya A Koizumi H Kuse N Oka S Duda A Prendergast A Crawford H Leslie A Brumme Z Brumme C Allen T Brander C Kaslow R Tang J Hunter E Allen S Mulenga J Branch S Roach T John M Mallal S Ogwu A Shapiro R Prado J G Fidler S Weber J Pybus O G Klenerman P Ndung'u T Phillips R Heckerman D Harrigan P R Walker B D Takiguchi M Goulder P | 2009 | Nature2009，458，7238： | 1 |
| 5 | Comparative Life- cycleAir Emissions of Coal,Domestic Natural Gas,LNG,and SNG forElectricity Generation 显示文摘 | Jaramillo P Griffin W M Matthews H S | 2007 | Environmental Science & Technology2007，41，17： | 1 |
| 6 | Variable structure control of nonlinear multivariable systems: a tutorial 显示文摘 | de Carlo R A Zak S H Matthews G P | 1988 | Proceedings of the IEEE1988，76，3： | 1 |
| 7 | Morphology and the Internal Structure of Words 显示文摘 | DEVLIN J T JAMISON H L MATTHEWS P M | 2004 | Pro- ceedings of the National Academy of Sciences2004，101，14： | 1 |
| 8 | Evaluation ofthe biocompatibility of a chitosan scaffold in mice 显示文摘 | VandeYord P J Matthew H W DeSilva S P | 2002 | BiomedMater Res2002，59，3： | 1 |
| 9 | The epidemiology of nephrotoxicity associated with conventional amphotericin B therapy显示文摘 | Stephan Harbarth Stanley L Pestotnik James F Lloyd John P Burke Matthew H Samore | 2001 | The American Journal of Medicine2001，，： | 1 |
| 10 | Ultrasonically assisted synthesis and degradation of poly ( dimethyl siloxane) 显示文摘 | Gareth J P Matthew P H Emma N K W | 1996 | Polymer1996，37，12： | 1 |
| 11 | 显示文摘 | VandeVord P J Matthew H W DeSilva S P | 2002 | Journal of Biomedical Materials Research2002，59，3： | 1 |
| 12 | Changes in Neutrophil Surface Receptor expression,Degranulation,and Respiratory Burst Activity Following Moderate and High Intensity Exercise显示文摘 | Jonathan P Gary W Matthew H | | 0，，02： | 1 |
| 13 | Laser capture microdissection (LCM) and comparative microarray expression analysis of syncytial cells isolated from incompatible and compatible soybean (Glycine max) roots infected by soybean cyst nematode (Heterodera glycines)显示文摘 | Klink V P Overall C C Alkharouf N MacDonald M H Matthews B F | | 0，，06： | 1 |
| 14 | Experimental studies in the LENS supersonic and hypersonic tunnels for hypervelocity vehicle performance and code validation 显示文摘 | Michael S H Timothy P W Matthew M | 2008 | AIAA2008，2505，： | 1 |
| 15 | Variable structure control of nonlinear multivariable systems: A tutorial 显示文摘 | DeCarlo R A Zak S H Matthews G P | 1988 | IEEE Proceeding1988，76，： | 1 |
| 16 | Nucleotide sequence and analysis and comparison of the structural genes for Shiga-like toxin i and Shiga-like toxin Ⅱ encoded by bacteriophages from Escherichia coli 933显示文摘 | MATTHEW P J ROGER J H ALISON D O | 1987 | FEMS Microbiology Letters1987，44，10： | 1 |
| 17 | Investigating employee perceptions of a framework of safety culture maturity显示文摘 | MATTHEW L DIANNE P PATRICK H | 2006 | Safety Science2006，44，： | 1 |
| 18 | Inflammation-associated lysophospholipids as ligands for CD1D-restricted T cells in human cancer显示文摘 | Chang DH Deng H Matthews P | 2008 | Blood2008，112，4： | 1 |
| 19 | Evaluation of the biocompatibility of a chitosan scaffold in mice显示文摘 | VandeVord P J Matthew H W T DeSilva S P | 2002 | J Biomed Mater Res2002，59，3： | 1 |
| 20 | Prediction of mammalian microRNA targets显示文摘 | Lewis B P Shih I H Matthew W J | 2003 | Cell2003，115，： | 1 |
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