These models are usually divided into two main categories: The diet-induced models and the genetically modified models (transgenic or knockout models). Historically, several animal models have been developed to represent the pathophysiology, morphological findings, biochemical changes, and clinical features of human NAFLD/NASH. A likely contributor to the absence of therapeutics is the paucity of preclinical models resembling human NAFLD/NASH. There are currently no pharmacological agents specifically approved for the treatment of NASH and disease management is consequently focused on the correction of underlying risk factors ( e.g., obesity, insulin resistance and dyslipidemia). The pathogenesis of NASH is described by the “two-hit” hypothesis, the first hit being fat accumulation in hepatocytes, while the “second hit”, e.g., oxidative stress, apoptosis or mitochondrial dysfunction, causes development of inflammation and fibrosis. NAFLD is considered the hepatic manifestation of the metabolic syndrome and covers a variety of pathologies ranging from simple hepatic steatosis (accumulation of triglycerides in hepatocytes) to nonalcoholic steatohepatitis (NASH), characterized by inflammation, cellular ballooning and fibrosis in varying degrees. It is generally accepted that along with increasing rates of obesity, type 2 diabetes and metabolic syndrome, the incidence and prevalence of patients with nonalcoholic fatty liver disease (NAFLD) continues to rise. Notably, fibrosis stage was significantly ( P < 0.001) increased in ob/ ob-NASH mice, when compared to DIO-NASH mice.ĬONCLUSION: 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. 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). 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. 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. Overall, the metabolic NASH phenotype was more pronounced in ob/ ob-NASH vs DIO-NASH mice. The diet also induced clear histological features of NASH including hepatosteatosis and fibrosis. 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. Steatosis and fibrosis were also quantified using percent fractional area. Non-alcoholic fatty liver disease activity score (NAS) (steatosis/inflammation/ballooning degeneration) and fibrosis were scored. Metabolic parameters, plasma liver enzymes and lipids (total cholesterol, triglycerides) as well as hepatic lipids and collagen content were measured by biochemical analysis. Global gene expression in liver tissue was assessed by RNA sequencing and bioinformatics. 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. After the diet-induction period, mice were liver biopsied and a blinded histological assessment of steatosis and fibrosis was conducted. A normal chow diet served as control in C57 mice (lean chow) and ob/ ob mice ( ob/ ob chow). 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. AIM: To characterize development of diet-induced nonalcoholic steatohepatitis (NASH) by performing liver biopsy in wild-type and genetically obese mice.
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