AIM: To characterize development of diet-induced nonalcoholic steatohepatitis (NASH) by performing liver 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 fibrosis 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 bioinformatics. Metabolic parameters, plasma liver enzymes and lipids (total cholesterol, triglycerides) as well as hepatic lipids and collagen content were measured by biochemical analysis. Non-alcoholic fatty liver disease activity score (NAS) (steatosis/inflammation/ballooning degeneration) and fibrosis were scored. Steatosis and fibrosis were also quantified using percent fractional area. RESULTS: Diet-induction for 26 and 12 wk in DIO-NASH 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 vs 4.7 ± 0.4, P < 0.001 compared to lean chow) and ob/ob-NASH mice (2.4 ± 0.3 vs 6.3 ± 0.2, P < 0.001 compared 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 < 0.001 compared 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 diet-induced DIO-NASH and ob/ob-NASH mouse models with biopsy-confirmed individual disease staging as a preclinical platform for evaluation of novel NASH therapeutics.
AIM: To characterize development of diet-induced nonalcoholic steatohepatitis (NASH) by performing liver biopsy in wild-type and genetically obesemice. 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/obmice (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 fibrosis 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 bioinformatics. Metabolic parameters, plasma liver enzymes and lipids (total cholesterol, triglycerides) as well as hepatic lipids and collagen content were measured by biochemical analysis. Non-alcoholic fatty liver disease activity score (NAS) (steatosis/inflammation/ballooning degeneration) and fibrosis were scored. Steatosis and fibrosis were also quantified using percent fractional area. RESULTS: Diet-induction for 26 and 12 wk in DIO-NASH 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 vs 4.7 ± 0.4, P < 0.001 compared to lean chow) and ob/ob-NASH mice (2.4 ± 0.3 vs 6.3 ± 0.2, P < 0.001 compared 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 < 0.001 compared 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 diet-induced DIO-NASH and ob/ob-NASH mouse models with biopsy-confirmed individual disease staging as a preclinical platform for evaluation of novel NASH therapeutics.
Authors: Jason R Clapper; Michelle D Hendricks; Guibao Gu; Carrie Wittmer; Carrie S Dolman; John Herich; Jennifer Athanacio; Christiane Villescaz; Soumitra S Ghosh; Joseph S Heilig; Carolyn Lowe; Jonathan D Roth Journal: Am J Physiol Gastrointest Liver Physiol Date: 2013-07-25 Impact factor: 4.052
Authors: Alexander Dobin; Carrie A Davis; Felix Schlesinger; Jorg Drenkow; Chris Zaleski; Sonali Jha; Philippe Batut; Mark Chaisson; Thomas R Gingeras Journal: Bioinformatics Date: 2012-10-25 Impact factor: 6.937
Authors: Ekihiro Seki; Samuele De Minicis; Christoph H Osterreicher; Johannes Kluwe; Yosuke Osawa; David A Brenner; Robert F Schwabe Journal: Nat Med Date: 2007-10-21 Impact factor: 53.440
Authors: Jacob G Zeevaart; Ligong Wang; Vinay V Thakur; Cheryl S Leung; Julian Tirado-Rives; Christopher M Bailey; Robert A Domaoal; Karen S Anderson; William L Jorgensen Journal: J Am Chem Soc Date: 2008-06-28 Impact factor: 15.419
Authors: Laura H Tetri; Metin Basaranoglu; Elizabeth M Brunt; Lisa M Yerian; Brent A Neuschwander-Tetri Journal: Am J Physiol Gastrointest Liver Physiol Date: 2008-09-04 Impact factor: 4.052
Authors: Manuel Baader; Tom Bretschneider; Andre Broermann; Joerg F Rippmann; Birgit Stierstorfer; Christian A Kuttruff; Michael Mark Journal: Br J Pharmacol Date: 2018-01-17 Impact factor: 8.739
Authors: Philipp Kasper; Saida Breuer; Thorben Hoffmann; Christina Vohlen; Ruth Janoschek; Lisa Schmitz; Sarah Appel; Gregor Fink; Christoph Hünseler; Alexander Quaas; Münevver Demir; Sonja Lang; Hans-Michael Steffen; Anna Martin; Christoph Schramm; Martin Bürger; Esther Mahabir; Tobias Goeser; Jörg Dötsch; Eva Hucklenbruch-Rother; Inga Bae-Gartz Journal: Cells Date: 2021-05-19 Impact factor: 6.600
Authors: 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 Journal: World J Gastroenterol Date: 2018-01-14 Impact factor: 5.742
Authors: Kirstine S Tølbøl; Maria Nb Kristiansen; Henrik H Hansen; Sanne S Veidal; Kristoffer Tg Rigbolt; Matthew P Gillum; Jacob Jelsing; Niels Vrang; Michael Feigh Journal: World J Gastroenterol Date: 2018-01-14 Impact factor: 5.742