Non-alcoholic steatohepatitis (NASH) is a severe form of non-alcoholic fatty liver disease (NAFLD), characterized by excessive fat accumulation, inflammation, and liver cell damage. This condition can progress to advanced scarring, known as fibrosis, potentially leading to cirrhosis or liver failure. The increasing global prevalence of NASH highlights the need for effective treatments and a deeper understanding of its progression. Developing these treatments relies on animal models to study the disease and test potential therapies.
Developing NASH in Mice
Researchers employ various methods to induce NASH-like conditions in mice. One common approach involves diet-induced models, where specific dietary compositions promote liver pathology. High-fat diets (HFDs) are frequently used, leading to obesity, insulin resistance, and hepatic steatosis. These diets often contain a high percentage of calories from fat, such as 60% fat, which can induce steatosis and moderate NASH.
Western diets, high in fat, sugar, and cholesterol, are another prevalent diet-induced model. These diets mimic human eating patterns and can induce steatohepatitis, obesity, and insulin resistance. For instance, a Western diet combined with high-fructose corn syrup can lead to obesity, glucose intolerance, and NASH with fibrosis.
A more specialized diet, the Gubra-Amylin NASH (GAN) diet, is formulated with 40% high-fat, 22% high-fructose, and 2% high-cholesterol. This diet is designed to resemble the Amylin Liver NASH (AMLN) diet but without trans-fats. The GAN diet induces biopsy-confirmed fibrotic NASH in mice, including increased weight gain and impaired glucose tolerance.
Genetic modifications also play a role in developing NASH mouse models, mimicking human genetic susceptibilities. These models involve altering specific genes, such as those involved in lipid metabolism or inflammation, to predispose mice to liver disease. Some genetically modified mice spontaneously develop liver disease, useful for studying underlying pathology. Combined approaches, using diet and genetic modifications together, can create models that more closely resemble the complex, multifactorial nature of human NASH. For example, certain genetically modified mice on high-fat diets develop metabolic syndrome-like profiles and advanced fibrosis, reflecting key pathways of human pathology.
Pathological Features of Mouse Models
NASH mouse models exhibit several key histological features that mirror the progression of human NASH. One prominent feature is steatosis, the abnormal accumulation of fat droplets within liver cells. This fat buildup can be macrovesicular or microvesicular, with macrovesicular steatosis being more common in NAFLD.
Beyond fat accumulation, inflammation is a hallmark of NASH, characterized by inflammatory cells and markers within the liver. This inflammatory response contributes to liver injury and disease progression. Hepatocyte ballooning, the characteristic swelling and degeneration of liver cells, is another significant pathological finding. This cellular damage is often observed in early stages of the disease.
The development of scar tissue, or fibrosis, indicates disease progression in NASH. Fibrosis can range from mild scarring to advanced stages, potentially leading to cirrhosis. Researchers assess these features through various histological methods, examining liver tissue for steatosis, ballooning, inflammation, and fibrosis. Biochemical markers are also measured to confirm the presence and severity of NASH in these models.
Evaluating Model Utility
Researchers carefully select and assess NASH mouse models based on specific research objectives. The study’s purpose dictates the choice of model, whether the focus is on early steatosis, the inflammatory response, fibrosis progression, or testing potential drug candidates. Some models excel at mimicking specific aspects or stages of the disease, making them more suitable for certain investigations.
No single mouse model can fully replicate the complexity of human NASH, which is a multifactorial disease. Different models show varying degrees of disease development and severity of hepatic fibrosis. For instance, while some models develop advanced fibrosis, they may not fully reflect the human disease’s etiology or broader pathology.
Therefore, researchers must interpret findings from mouse models with careful consideration of their specific limitations and strengths. The outcomes from these preclinical studies inform and guide human clinical trials and drug development efforts. The aim is to choose models that provide the most relevant insights into disease mechanisms and therapeutic interventions for human NASH.