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.
Highlights
Nonalcoholic fatty liver disease (NAFLD) is the most prevalent liver disease in Western society [1]
The metabolic profile associated with human nonalcoholic steatohepatitis (NASH) was better mimicked by Western diet
Various mechanisms implicated in human NASH pathogenesis/progression were less robust in the Western diet model, including oxidative stress, Endoplasmic reticulum (ER) stress, autophagy deregulation, and hedgehog pathway activation
Summary
Nonalcoholic fatty liver disease (NAFLD) is the most prevalent liver disease in Western society [1]. The majority of patients will have a benign evolution, up to 25% develop potentially progressive liver damage, dubbed nonalcoholic steatohepatitis (NASH). NAFLD is a very slowly progressive disease, which hinders prospective observational studies. Given these challenges, animal models that mimic human pathology are a necessity. The perfect animal model would develop NAFLD in the context of key risk factors for the human condition (i.e., obesity and the metabolic syndrome, MS), eventually manifest all histological features of NASH, progress to advanced liver fibrosis, and be susceptible to hepatocellular carcinoma. Non-alcoholic steatohepatitis (NASH), the potentially progressive form of nonalcoholic fatty liver disease (NAFLD), is the pandemic liver disease of our time. We aimed to compare features of NASH in the two most widely-used mouse models: methionine-choline deficient (MCD) diet and Western diet
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