Mouse models in non-alcoholic fatty liver disease and steatohepatitis research

Abstract

Non-alcoholic fatty liver disease (NAFLD) represents a histological spectrum of liver disease associated with obesity, diabetes and insulin resistance that extends from isolated steatosis to steatohepatitis and cirrhosis. As well as being a potential cause of progressive liver disease in its own right, steatosis has been shown to be an important cofactor in the pathogenesis of many other liver diseases. Animal models of NAFLD may be divided into two broad categories: those caused by genetic mutation and those with an acquired phenotype produced by dietary or pharmacological manipulation. The literature contains numerous different mouse models that exhibit histological evidence of hepatic steatosis or, more variably, steatohepatitis; however, few replicate the entire human phenotype. The genetic leptin-deficient (ob/ob) or leptin-resistant (db/db) mouse and the dietary methionine/choline-deficient model are used in the majority of published research. More recently, targeted gene disruption and the use of supra-nutritional diets to induce NAFLD have gained greater prominence as researchers have attempted to bridge the phenotype gap between the available models and the human disease. Using the physiological processes that underlie the pathogenesis and progression of NAFLD as a framework, we review the literature describing currently available mouse models of NAFLD, highlight the strengths and weaknesses of established models and describe the key findings that have furthered the understanding of disease pathogenesis.

Figure 1

The ‘two-hit’ hypothesis for the pathogenesis on non-alcoholic fatty liver disease. The progression from normal healthy liver to steatohepatitis is in a stepwise fashion involving first the development of obesity and insulin resistance (which leads to fatty change) and later hepatic inflammation. Some of the available models and pathogenic processes are also summarized.

Figure 2

Hepatic lipid metabolism and the development of steatosis. In the absorptive state, dietary triglycerides (TG) are transported in the circulation as chylomicrons, LPL-mediated degradation releases LCFA. In the postabsorptive (fasting) state, insulin levels fall, and HSL releases LCFA from adipose tissue. In addition to absorbing circulating LCFA, hepatocytes synthesize LCFA from dietary carbohydrate under control of SREBP-1c and ChREBP. Hepatic clearance of fatty acids depends on oxidation in the mitochondria and peroxisomes (β-oxidation) or microsomes (ω-oxidation) to generate acetyl CoA for entry into Krebs cycle. Excess fatty acids are re-esterified to TG for export into the circulation as VLDL. Points at which disruption may produce non-alcoholic fatty liver disease are highlighted and discussed in the text. ApoB100, apolipoprotein B100; ChREBP, carbohydrate response element-binding protein; CPT1, carnitine palmonitoyl transferase 1; HSL, hormone sensitive lipase; LCFA, long-chain fatty acids; LPL, lipoprotein lipase; MTT, microsomal TG transfer protein; PPARα, peroxisome proliferator-activated receptor a; SREBP-1c, sterol regulatory element-binding protein 1c; VLDL, very low density lipoprotein.