Diet-Induced Models of Non-Alcoholic Fatty Liver Disease: Food for Thought on Sugar, Fat, and Cholesterol

Abstract

Non-alcoholic fatty liver disease (NAFLD) affects approximately 1 in 4 people worldwide and is a major burden to health care systems. A major concern in NAFLD research is lack of confidence in pre-clinical animal models, raising questions regarding translation to humans. Recently, there has been renewed interest in creating dietary models of NAFLD with higher similarity to human diets in hopes to better recapitulate disease pathology. This review summarizes recent research comparing individual roles of major dietary components to NAFLD and addresses common misconceptions surrounding frequently used diet-based NAFLD models. We discuss the effects of glucose, fructose, and sucrose on the liver, and how solid vs. liquid sugar differ in promoting disease. We consider studies on dosages of fat and cholesterol needed to promote NAFLD versus NASH, and discuss important considerations when choosing control diets, mouse strains, and diet duration. Lastly, we provide our recommendations on amount and type of sugar, fat, and cholesterol to include when modelling diet-induced NAFLD/NASH in mice.

Keywords: NAFLD; NASH; cholesterol; dietary model; high-fat diet; liquid sugar; liver; solid sugar.

Figure 1

Dietary sugars promoting either hepatic steatosis or inflammation and fibrosis. Steatosis can be induced by liquid fructose (10–30% w/v) or by a mixture of glucose and fructose (30% + 30% w/w solid, or 10% w/v high-fructose corn syrup in water) alone or in combination with high-fat content. 60% liquid fructose induces both steatosis and fibrosis, while 60% solid fructose promotes hepatic inflammation. Liquid sucrose (10–30% w/v), with or without high fat, stimulates hepatic inflammation, with higher doses (40–50% w/v) promoting fibrosis.

Figure 2

Summary of key dietary components contributions when modeling non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) in rodents. Inclusion of solid sugar stimulates hepatic inflammation compared to liquid sugar, whereas liquid sugar contributes more to hepatic lipid accumulation. Using solid sugars requires higher dosage to induce liver damage compared to liquid sources. High fat is required to stimulate obesity; however, at quantities above 50% kcal there is a plateau in weight gain. Inclusion of cholesterol promotes hepatic inflammation and fibrosis. Evidence suggests that the optimal dosage of cholesterol for mice is between 0.5% and 1%, but may vary between mouse strains. Below 0.5%, diets fail to induce inflammation and NASH, while above 1% prevents weight gain.