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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 | INT-767 improves histopathological features in a dietinduced ob/ob mouse model of biopsy-confirmed nonalcoholic steatohepatitis显示文摘AIM To characterize the efficacy of the dual FXR/TGR5 receptor agonist INT-767 upon histological endpoints in a rodent model of diet-induced and biopsy-confirmed non-alcoholic steatohepatitis(NASH).METHODS The effects of INT-767 on histological features of NASH were assessed in two studies using Lep^(ob/ob)(ob/ob) NASH mice fed the AMLN diet(high fat with transfat, cholesterol and fructose). In a proof-of-conceptstudy, Lep^(ob/ob)(ob/ob) NASH mice were first dosed with INT-767(3 or 10 mg/kg for 8 wk). A second ob/ob NASH study compared INT-767(3 and 10 mg/kg) to obeticholic acid(OCA)(10 or 30 mg/kg; 16 wk). Primary histological endpoints included qualitative and quantitative assessments of NASH. Other metabolic and plasma endpoints were also assessed. A comparative assessment of INT-767 and OCA effects on drug distribution and hepatic gene expression was performed in C57 Bl/6 mice on standard chow. C57 Bl/6 mice were orally dosed with INT-767 or OCA(1-30 mg/kg) for 2 wk, and expression levels of candidate genes were assessed by RNA sequencing and tissue drug levels were measured by liquid chromatography tandem-mass spectrometry.RESULTS INT-767 dose-dependently(3 and 10 mg/kg, PO, QD, 8 wk) improved qualitative morphometric scores on steatohepatitis severity, inflammatory infiltrates and fibrosis stage. Quantitative morphometric analyses revealed that INT-767 reduced parenchymal collagen area, collagen fiber density, inflammation(assessed by Galectin-3 immunohistochemistry) and hepatocyte lipid droplet area following INT-767 treatment. In a comparative study(16 wk), the FXR agonists OCA(10 and 30 mg/kg) and INT-767(3 and 10 mg/kg) both improved NASH histopathology, with INT-767 exerting greater therapeutic potency and efficacy than OCA. Mechanistic studies suggest that both drugs accumulate similarly within the liver and ileum, however, the effects of INT-767 may be driven by enhanced hepatic, but not ileal, FXR function. CONCLUSION These findings confirm the potential utility of FXR and dual FXR/TGR5 activation as disease intervention strategies in NASH. | Jonathan D Roth Michael Feigh Sanne S Veidal Louise KD Fensholdt Kristoffer T Rigbolt Henrik H Hansen Li C Chen Mathieu Petitjean Weslyn Friley Niels Vrang Jacob Jelsing Mark Young | 2018 | World Journal of Gastroenterology2018，24，2： | 7 |
| 3 | Effects of liraglutide and sibutramine on food intake, palatability, body weight and glucose tolerance in the gubra DlO-rats显示文摘 | Gitte HANSEN Jacob JELSlNG Niels VRANG | 2012 | Acta Pharmacologica Sinica2012，33，2： | 6 |
| 4 | 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 |
| 5 | Towards a standard diet-induced and biopsy-confirmed mouse model of non-alcoholic steatohepatitis: Impact of dietary fat source显示文摘BACKGROUND The trans-fat containing AMLN(amylin liver non-alcoholic steatohepatitis,NASH)diet has been extensively validated in C57BL/6J mice with or without the Lep^ob/Lep^ob(ob/ob)mutation in the leptin gene for reliably inducing metabolic and liver histopathological changes recapitulating hallmarks of NASH.Due to a recent ban on trans-fats as food additive,there is a marked need for developing a new diet capable of promoting a compatible level of disease in ob/ob and C57BL/6J mice.AIM To develop a biopsy-confirmed mouse model of NASH based on an obesogenic diet with trans-fat substituted by saturated fat.METHODS Male ob/ob mice were fed AMLN diet or a modified AMLN diet with trans-fat(Primex shortening)substituted by equivalent amounts of palm oil[Gubra amylin NASH,(GAN)diet]for 8,12 and 16 wk.C57BL/6J mice were fed the same diets for 28 wk.AMLN and GAN diets had similar caloric content(40%fat kcal),fructose(22%)and cholesterol(2%)level.RESULTS The GAN diet was more obesogenic compared to the AMLN diet and impaired glucose tolerance.Biopsy-confirmed steatosis,lobular inflammation,hepatocyte ballooning,fibrotic liver lesions and hepatic transcriptome changes were similar in ob/ob mice fed the GAN or AMLN diet.C57BL/6J mice developed a mild to moderate fibrotic NASH phenotype when fed the same diets.CONCLUSION Substitution of Primex with palm oil promotes a similar phenotype of biopsyconfirmed NASH in ob/ob and C57BL/6J mice,making GAN diet-induced obese mouse models suitable for characterizing novel NASH treatments. | Michelle L Boland Denise Oro Kirstine S T■lb■l Sebastian T Thrane Jens Christian Nielsen Taylor S Cohen David E Tabor Fiona Fernandes Andrey Tovchigrechko Sanne S Veidal Paul Warrener Bret R Sellman Jacob Jelsing Michael Feigh Niels Vrang James L Trevaskis Henrik H Hansen | 2019 | World Journal of Gastroenterology2019，25，33： | 3 |
| 6 | Anti-HIV type 1 activity of 3'-fluoro-3'-deoxythymidine for several different multidrug- resistant mutants显示文摘 | Kim EY Vrang L Oberg B | 2001 | AIDS Res Hum Retroviruses2001，17，5： | 1 |
| 7 | Neurochemical character-ization of hypothalamic cocaine-amphetamine-regulated transcript neu-rons显示文摘 | VRANG N LARSEN P J CLAUSEN J T | 1999 | J Neurosci1999，19，10： | 1 |
| 8 | Afferent projections to the hamster intergeniculate leaflet demonstrated by retrograde and anterograde tracing显示文摘 | Vrang N Mrosovsky N Mikkelsen JD | 2003 | Brain Research Bulletin2003，59，26： | 1 |
| 9 | Optimization of signal peptide SP310 for heterologous protein production in Lactococcus lactis显示文摘 | Ravn P Arnau J Madsen S M Vrang A Israelsen H | 2003 | Microbiology2003，149，8： | 1 |
| 10 | Central administration of ghrdin and agouti-related protein(83-132) increases food intake and decreases spontaneous locomotor acdvity in rats 显示文摘 | Tang-Christensen M Vrang N Ortmann S | 2004 | Endocrinology2004，145，10： | 1 |
| 11 | Glucagon-like peptide 1 (7-36) amide's central inhibition of feeding and peripheral inhibition of drinking are abolished by neonatal monosodium glutamate treatment显示文摘 | Tang-Christensen M Vrang N Larsen PL | | 0，，： | 1 |
| 12 | Characterization of brainstem preproglucagon projections to the paraventricular and dorsomedial hypothalamic nuclei显示文摘 | Vrang N Hansen M Larsen PJ | 2007 | Brain Res2007，1149，： | 1 |
| 13 | Preproglucagon derived peptides GLP-1,GLP-2 and oxyntomodulin in the CNS:role of peripherally secreted and centrally produced peptides显示文摘 | Vrang N Larsen PJ | 2010 | Prog Neurobiol2010，92，3： | 1 |
| 14 | Cloning and partial characterization of regulated promoters from Lactococcus lactis Tn917 -lacZ integrants with the new promoter probe vector pAK80 显示文摘 | ISRAELSEN H Madsen S M Vrang A | 1995 | Appl Environ Microbiol1995，61，： | 1 |
| 15 | The once-daily human GLP- 1 analog, liraglutide, reduces olanzapine-induced weight gain and glucose intolerance显示文摘 | Lykkegaard K Larsen PJ Vrang N | 2008 | Schizophr Res2008，103，： | 1 |
| 16 | Die rheologischen Sigenschaften Von Weizenteigen unter Zusatz Von diacetyliertem Weinsaureester 显示文摘 | Nybo Jensen B Vrang C | 1971 | Brot Gebaeck1971，25，： | 1 |
| 17 | Persistence of nonphotic phase shifts in hamsters after serotomin depletion in the suprachiasmatic nucleus显示文摘 | Niels Vrang Mrosovsky NI | 1996 | Brain Res1996，741，： | 1 |
| 18 | Effects ofleptin on arcuate pro-opiomelanocortin and cocaine-amphetamine-regula-ted transcript expression are independent of circulating levels of corticos-terone显示文摘 | VRANG N KRISTENSEN P TANG-CHRISTENSEN M | 2002 | J Neuroendocrinol2002，14，11： | 1 |
| 19 | Glucagon-like peptide 1 (7-36) amide's central inhibition of feeding and peripheral inhibition of drinking are abolished by neonatal monosodium glutamate treatment显示文摘 | Tang-Christensen M Vrang N Lamen PJ | 1998 | Diabetes1998，47，4： | 1 |
| 20 | Recombinant CART peptide induces c-fos expression in central areas involved in control of feeding behaviour 显示文摘 | Vrang N Tang CM Larsen PJ | 1999 | Brain Res1999，818，2： | 1 |
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