Genetically modified mouse models for the study of nonalcoholic fatty liver disease

Abstract

Nonalcoholic fatty liver disease (NAFLD) is associated with obesity, insulin resistance, and type 2 diabetes. NAFLD represents a large spectrum of diseases ranging from (1) fatty liver (hepatic steatosis); (2) steatosis with inflammation and necrosis; to (3) cirrhosis. The animal models to study NAFLD/nonalcoholic steatohepatitis (NASH) are extremely useful, as there are still many events to be elucidated in the pathology of NASH. The study of the established animal models has provided many clues in the pathogenesis of steatosis and steatohepatitis, but these remain incompletely understood. The different mouse models can be classified in two large groups. The first one includes genetically modified (transgenic or knockout) mice that spontaneously develop liver disease, and the second one includes mice that acquire the disease after dietary or pharmacological manipulation. Although the molecular mechanism leading to the development of hepatic steatosis in the pathogenesis of NAFLD is complex, genetically modified animal models may be a key for the treatment of NAFLD. Ideal animal models for NASH should closely resemble the pathological characteristics observed in humans. To date, no single animal model has encompassed the full spectrum of human disease progression, but they can imitate particular characteristics of human disease. Therefore, it is important that the researchers choose the appropriate animal model. This review discusses various genetically modified animal models developed and used in research on NAFLD.

Inhibiting Monoacylglycerol Acyltransferase 1 Ameliorates Hepatic Metabolic Abnormalities but Not Inflammation and Injury in Mice

“…Typical rodent high fat diets employed to cause obesity and produce hepatic steatosis are usually not associated with development of severe liver inflammation and fibrosis in mice unless they are fed for extremely long durations. In the past few years, attempts have been made to induce liver injury by using a number of permutations of the high fat diet formula (35) and/or by superimposing other insults with the dietary regimen (36 -41). Studies utilizing a combination of high fat diets containing high levels of trans fatty acids, often in combination with increased dietary fructose or the addition of cholesterol have enjoyed success at provoking liver injury (15,42,43).…”

Ethnic Differences in the Link Between Insulin Resistance and Elevated ALT

“…17 In this sense, previous studies would suggest that NAFLD may be a cause of worsening MetS. Conversely, the underlying processes of obesity, inflammation, and adipokines that drive abnormalities associated with MetS are also associated with NAFLD in basic science models 51,52 and may contribute to liver fat accumulation through related pathways. 15 In this sense, individuals with a high degree of IR from these processes would be expected to have a higher risk of NAFLD, highlighting how NAFLD may be an effect of processes behind MetS.…”

Animal models of chronic liver diseases

“…Those animal models have been extensively reviewed by others (3,39,59,99,113,131,164,181), and thus only the most commonly used and some newly described models are mentioned here. NASH models can be roughly classified into three broad categories: 1) genetic models, 2) dietary models, and 3) models combining genetic factors with nutritional factors.…”