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| 1 | Obese diet-induced mouse models of nonalcoholic steatohepatitis-tracking disease by liver biopsy显示文摘AIM:To characterize development of diet-induced nonalcoholic steatohepatitis(NASH)by performing live biopsy in wild-type and genetically obese mice.METHODS:Male wild-type C57BL/6J(C57)mice(DIO NASH)and male Lep ob/Lep ob(ob/ob)mice(ob/ob-NASH were maintained on a diet high in trans-fat(40%)fructose(22%)and cholesterol(2%)for 26 and 12 wk respectively.A normal chow diet served as control in C57 mice(lean chow)and ob/ob mice(ob/ob chow)After the diet-induction period,mice were liver biopsied and a blinded histological assessment of steatosis and fibrosis was conducted.Mice were then stratified into groups counterbalanced for steatosis score and fibrosi stage and continued on diet and to receive daily PO dosing of vehicle for 8 wk.Global gene expression in liver tissue was assessed by RNA sequencing and bioin formatics.Metabolic parameters,plasma liver enzyme and lipids(total cholesterol,triglycerides)as well a hepatic lipids and collagen content were measured b biochemical analysis.Non-alcoholic fatty liver disease activity score(NAS)(steatosis/inflammation/ballooningdegeneration)and fibrosis were scored.Steatosis and fibrosis were also quantified using percent fractional area.RESULTS:Diet-induction for 26 and 12 wk in DIONASH and ob/ob-NASH mice,respectively,elicited progressive metabolic perturbations characterized by increased adiposity,total cholesterol and elevated plasma liver enzymes.The diet also induced clear histological features of NASH including hepatosteatosis and fibrosis.Overall,the metabolic NASH phenotype was more pronounced in ob/ob-NASH vs DIO-NASH mice.During the eight week repeated vehicle dosing period,the metabolic phenotype was sustained in DIO-NASH and ob/ob-NASH mice in conjunction with hepatomegaly and increased hepatic lipids and collagen accumulation.Histopathological scoring demonstrated significantly increased NAS of DIO-NASH mice(0 vs4.7±0.4,P<0.001 compared to lean chow)and ob/ob-NASH mice(2.4±0.3 vs 6.3±0.2,P<0.001compared to ob/ob chow),respectively.Furthermore,fibrosis stage was significantly elevated for DIO-NASH mice(0 vs 1.2±0.2,P<0.05 compared to lean chow)and ob/ob NASH(0.1±0.1 vs 3.0±0.2,P<0.001compared to ob/ob chow).Notably,fibrosis stage was significantly(P<0.001)increased in ob/ob-NASH mice,when compared to DIO-NASH mice.CONCLUSION:These data introduce the obese dietinduced DIO-NASH and ob/ob-NASH mouse models with biopsy-confirmed individual disease staging as a preclinical platform for evaluation of novel NASH therapeutics. | Maria Nicoline Baandrup Kristiansen Sanne Skovgard Veidal Kristoffer Tobias Gustav Rigbolt Kirstine Sloth Tolbol Jonathan David Roth Jacob Jelsing Niels Vrang Michael Feigh | 2016 | World Journal of Hepatology2016，8，16： | 10 |
| 2 | 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 |
| 3 | Airmonitoring of aldehydes by use of hydrazine reagents witha triazine backbone 显示文摘 | Kempter C Berkhoudt T W Tolbol Greve C | 2002 | Anal Bioanal Chem2002，372，56： | 1 |
| 4 | Air monito-ring of aldehydes by use of hydrazine reagents with a triazine backbone显示文摘 | Kempter C Berkhoudt T W Tolbol Greve C | | 0，，56： | 1 |
| 5 | Air monito-ring of aldehydes by use of hydrazine reagents with a triazine backbone显示文摘 | Kempter C Berkhoudt T W Tolbol Greve C | 2002 | Anal Bioanal Chem2002，372，56： | 1 |
| 6 | Air monito-ring of aldehydes by use of hydrazine reagents with a triazine backbone 显示文摘 | Kempter C Berkhoudt T W Tolbol Greve C | 2002 | Anal Bioanal Chem2002，372，56： | 1 |
| 7 | A ir monitoring of aldehydes by use of hydrazine reagents with a trizine backbone显示文摘 | Kempter C Berkhoudt T W Tolbol Greve C | 2002 | Anal Bioanal Chem2002，372，56： | 1 |
| 8 | Air monitoring of aldehydes by use of hydrazine reagents with a triazine backbone 显示文摘 | KEMPTER C BERKHOUDT T W TOLBOL Greve C | 2002 | Anal Bioanal Chem2002，372，5： | 1 |
| 9 | Robust 1D inversion and analysis of helicopter electromagnetic (HEM) data 显示文摘 | Tolboll R J Christensen N B | 2006 | Geophysics2006，71，2： | 1 |
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