Mouse Models of Diet-Induced Nonalcoholic Steatohepatitis Reproduce the Heterogeneity of the Human Disease

Abstract

Background and aimsNon-alcoholic steatohepatitis (NASH), the potentially progressive form of nonalcoholic fatty liver disease (NAFLD), is the pandemic liver disease of our time. Although there are several animal models of NASH, consensus regarding the optimal model is lacking. We aimed to compare features of NASH in the two most widely-used mouse models: methionine-choline deficient (MCD) diet and Western diet.MethodsMice were fed standard chow, MCD diet for 8 weeks, or Western diet (45% energy from fat, predominantly saturated fat, with 0.2% cholesterol, plus drinking water supplemented with fructose and glucose) for 16 weeks. Liver pathology and metabolic profile were compared.ResultsThe metabolic profile associated with human NASH was better mimicked by Western diet. Although hepatic steatosis (i.e., triglyceride accumulation) was also more severe, liver non-esterified fatty acid content was lower than in the MCD diet group. NASH was also less severe and less reproducible in the Western diet model, as evidenced by less liver cell death/apoptosis, inflammation, ductular reaction, and fibrosis. Various mechanisms implicated in human NASH pathogenesis/progression were also less robust in the Western diet model, including oxidative stress, ER stress, autophagy deregulation, and hedgehog pathway activation.ConclusionFeeding mice a Western diet models metabolic perturbations that are common in humans with mild NASH, whereas administration of a MCD diet better models the pathobiological mechanisms that cause human NAFLD to progress to advanced NASH.

Metabolic phenotype and adipose and liver features in a high-fat Western diet-induced mouse model of obesity-linked NAFLD

“…The high-fat Western diet-plus-liquid sugar consumption model of obesity in mice was originally developed as a model of NAFLD progression (3,19,39) and appears to model obese humans with mild NASH, as recently reported in a thorough analysis of the liver pathophysiology phenotype (21). Yet, it may be a good model for other chronic conditions associated with obesity such as diabetes, cardiovascular disease, and Alzheimer's disease.…”

Obesity, But Not High Fat Diet, Impairs Lymphatic Function

“…Our results are consistent with previous reports demonstrating that C57BL/6J mice become morbidly obese on HFD feeds, 8,9 while BALB/cJ and MSTN ln mice do not 21,22 even though serum FFA levels were significantly increased in all HFD-fed mice. 13,35 This approach is clinically relevant as the incidence and severity of obesity in patients is also highly variable and modulated by genetic factors. Our findings imply that obesity, but not HFD, is necessary for the development of lymphatic dysfunction since obesity-resistant mice maintained essentially normal lymphatic function despite prolonged exposure to HFD feeds.…”

Loss of miR-141/200c ameliorates hepatic steatosis and inflammation by reprogramming multiple signaling pathways in NASH

“…Hepatic lipid accumulation is one of the most prominent characteristic features of NASH and can induce further liver injury and inflammation. The MCD diet does not produce obesity or increased weight gain in mice, but steatosis develops within a short timeframe (18,19). H&E staining showed no overt differences in liver architecture between WT CD and miR-141 We next analyzed hepatic proteins and mRNAs associated with de novo lipogenesis and lipid transport.…”