New insights from rodent models of fatty liver disease

Abstract

Rodent models of fatty liver disease are essential research tools that provide a window into disease pathogenesis and a testing ground for prevention and treatment. Models come in many varieties involving dietary and genetic manipulations, and sometimes both. High-energy diets that induce obesity do not uniformly cause fatty liver disease; this has prompted close scrutiny of specific macronutrients and nutrient combinations to determine which have the greatest potential for hepatotoxicity. At the same time, diets that do not cause obesity or the metabolic syndrome but do cause severe steatohepatitis have been exploited to study factors important to progressive liver injury, including cell death, oxidative stress, and immune activation. Rodents with a genetic predisposition to overeating offer yet another model in which to explore the evolution of fatty liver disease. In some animals that overeat, steatohepatitis can develop even without resorting to a high-energy diet. Importantly, these models and others have been used to document that aerobic exercise can prevent or reduce fatty liver disease. This review focuses primarily on lessons learned about steatohepatitis from manipulations of diet and eating behavior. Numerous additional insights about hepatic lipid metabolism, which have been gained from genetically engineered mice, are also mentioned.

FIG. 1.

Impact of diet content and composition on hepatic steatosis. Schematized diagrams demonstrate the influence of diet content (A) and composition (B) on the evolution of hepatic steatosis in experimental animals. (A) Diets enriched to the extreme in either carbohydrate or fat tend not to provoke as much fatty liver as diets that contain a mixture of carbohydrate and fat. The outcome also depends upon the composition of carbohydrate and fat. (B) Diets that contain unsaturated fat tend to provoke hepatic steatosis even if paired with low amounts of carbohydrate or complex carbohydrate (e.g., starch). The degree of steatosis increases if unsaturated fat is paired with simple sugar. Diets that contain saturated fat cause relatively little steatosis when paired with low carbohydrate or complex carbohydrate. Steatosis increases when saturated fat is paired with sugar, but the slope of the increase may be smaller than that for unsaturated fat. It should be noted that most experimental formulas contain a mixture of carbohydrates and fats.

FIG. 2.

Saturated fat induces less steatosis than unsaturated fat. Photomicrographs depict liver histology in mice fed diets identical in nutrient composition except for fat. One diet was formulated with pure long-chain saturated fat (palmitate); the other was formulated with pure unsaturated fat (oleate). Diets were administered for 3 weeks.

FIG. 3.

Steatohepatitis induced by an MCD diet. Photomicrographs illustrate liver histology in mice fed a control diet (methionine-choline-sufficient, MCS) and a nutrient-matched MCD diet for 3 weeks. Mice fed the MCS diet have normal histology, whereas mice fed the MCD diet have steatosis and foci of hepatic inflammation.

FIG. 4.

Dietary sugar is critical to the pathogenesis of steatohepatitis in the MCD model. Photomicrographs illustrate liver histology in mice fed MCD diets containing glucose, fructose, or starch as carbohydrate. Diets were administered for 3 weeks. Mice fed MCD with glucose developed macrovesicular steatosis and had a mean ALT value of 471 IU/L. Mice fed MCD with fructose had mixed macrovesicular and microvesicular steatosis and had a mean ALT value of 928 IU/L. Mice fed MCD with starch had minimal steatosis and had a mean ALT of 93 IU/L. Data from (90, 91).