Animal models of nonalcoholic fatty liver disease/nonalcoholic steatohepatitis (original) (raw)
Related papers
Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature, 2017
Nonalcoholic fatty liver disease (NAFLD) constitutes a major health concern with the increasing incidence of obesity and diabetes in many Western countries, reaching a prevalence of up to 30% in the general population. Animal models have played a vital role in elucidating the pathophysiological mechanisms of NAFLD and continue to do so. A myriad of different models exists, each with its advantages and disadvantages. This review presents a brief overview of these models with a particular focus on the basic mechanisms and physical, biochemical and histological phenotype. Both nutritional and chemically induced, as well as genetic models are examined, including models combining different approaches.
Preclinical Models of Nonalcoholic Fatty Liver Disease
Journal of hepatology, 2017
Nonalcoholic fatty liver disease (NAFLD) can manifest as nonalcoholic fatty liver (NAFL) or nonalcoholic steatohepatitis (NASH). NASH is often associated with progressive fibrosis which can lead to cirrhosis and hepatocellular cancer (HCC). NASH is increasing as an etiology for end-stage liver disease as well as HCC. There are currently no approved therapies for NASH. A major barrier to development of therapeutics for NASH is the lack of preclinical models of disease that are appropriately validated to represent the biology and outcomes of human disease. There are many in vitro and animal models that have been developed. In vitro models do not fully capture the hepatic and extrahepatic mileu of human NASH and large animal models are expensive and logistically difficult to use. There is therefore considerable interest in the development and validation of mouse models for NAFLD including NASH. Several models based on varying genetic or dietary manipulations have been developed. The ma...
Genetic and Diet-Induced Animal Models for Non-Alcoholic Fatty Liver Disease (NAFLD) Research
International Journal of Molecular Sciences
A rapidly increasing incidence of non-alcoholic fatty liver disease (NAFLD) is noted worldwide due to the adoption of western-type lifestyles and eating habits. This makes the understanding of the molecular mechanisms that drive the pathogenesis of this chronic disease and the development of newly approved treatments of utmost necessity. Animal models are indispensable tools for achieving these ends. Although the ideal mouse model for human NAFLD does not exist yet, several models have arisen with the combination of dietary interventions, genetic manipulations and/or administration of chemical substances. Herein, we present the most common mouse models used in the research of NAFLD, either for the whole disease spectrum or for a particular disease stage (e.g., non-alcoholic steatohepatitis). We also discuss the advantages and disadvantages of each model, along with the challenges facing the researchers who aim to develop and use animal models for translational research in NAFLD. Bas...
Rodent Models of Nonalcoholic Fatty Liver Disease/Nonalcoholic Steatohepatitis
International Journal of Molecular Sciences, 2013
Research in nonalcoholic fatty liver disease (NAFLD), including nonalcoholic steatohepatitis (NASH), has been limited by the availability of suitable models for this disease. A number of rodent models have been described in which the relevant liver pathology develops in an appropriate metabolic context. These models are promising tools for researchers investigating one of the key issues of NASH: not so much why steatosis occurs, but what causes the transition from simple steatosis to the inflammatory, progressive fibrosing condition of steatohepatitis. The different rodent models can be classified into two large groups. The first includes models in which the disease is acquired after dietary or pharmacological manipulation, and the second, genetically modified models in which liver disease develops spontaneously. To date, no single rodent model has encompassed the full spectrum of human disease progression, but individual models can imitate particular
Genetically modified mouse models for the study of nonalcoholic fatty liver disease
World Journal of Gastroenterology, 2012
Nonalcoholic fatty liver disease (NAFL�) is associated with obesity, insulin resistance, and type 2 diabetes�� NAFL� 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 NAFL�/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 NAFL� is complex, genetically modified animal models may be a key for the treatment of NAFL��� 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 NAFL���
Murine Models of Nonalcoholic Fatty Liver Disease and Steatohepatitis
In 1980, Ludwig et al. �rst reported patients of steatohepatitis who lacked a history of excessive alcohol consumption but showed liver histology resembling alcoholic hepatitis and progression to cirrhosis of the liver accompanied by in�ammation and �brosis. e development of nonalcoholic steatohepatitis (NASH) is associated with obesity, diabetes mellitus, insulin resistance, and hyperlipidemia. However, the pathogenesis of NASH remains incomplete. A "multiple-hit" hypothesis for the pathogenesis of NASH based on an animal model has been proposed and remains a foundation for research in this �eld. �e review the important dietary and genetic animal models and discuss the pathogenesis of NASH. of Hindawi Publishing Corporation
Understanding mechanisms of the pathogenesis of nonalcoholic fatty liver disease
World journal of …, 2010
A central issue in the understanding of the pathogenesis of nonalcoholic fatty liver disease is the problem of the underlying mechanisms which are not fully understood. In the setting of excessive central adiposity, insulin resistance is the major underlying cause of fat accumulation in hepatocytes. Because of the difficulties with human trials, several animal models have been developed for this purpose mainly characterized as follows: genetically disturbed or murine fatty liver, methionine-choline deficient diet fed or murine steatohepatitis, and high-fat or sucrose diet fed models. Although these animal models have provided useful information, none of them accurately reflect genetic, metabolic and biochemical characteristics of the human disease.
Nonalcoholic Steatohepatitis: A Search for Factual Animal Models
BioMed Research International, 2015
Nonalcoholic fatty liver disease (NAFLD) is characterized by hepatic steatosis, which occurs in the absence of alcohol abuse. NAFLD can evolve into progressive liver injury and fibrosis in the form of nonalcoholic steatohepatitis (NASH). Several animal models have been developed to attempt to represent the morphological, biochemical, and clinical features of human NASH. The actual review presents a critical analysis of the most commonly used experimental models of NAFLD/NASH development. These models can be classified into genetic, nutritional, and a combination of genetic and nutritional factors. The main genetic models are ob/ob and db/db mutant mice and Zucker rats. The principal nutritional models employ methionine-and choline-deficient, high-fat, high-cholesterol and high-cholate, cafeteria, and high-fructose diets. Currently, associations between high-fructose and various compositions of high-fat diets have been widely studied. Previous studies have encountered significant difficulties in developing animal models capable of reproducing human NASH. Some models produce consistent morphological findings, but the induction method differs significantly compared with the pathophysiology of human NASH. Other models precisely represent the clinical and etiological contexts of this disease but fail to provide accurate histopathological representations mainly in the progression from steatosis to liver fibrosis.
An Accessible and Pragmatic Experimental Model of Nonalcoholic Fatty Liver Disease
Middle East Journal of Digestive Diseases, 2016
BACKGROUND There is no convenient cheap pragmatic experimental model for Nonalcoholic Fatty Liver Disease (NAFLD)/Nonalcoholic Steatohepatitis (NASH). Objective: Our objective was to create a pragmatic model of NAFLD/NASH. METHODS Sprague-Dawley rats were fed a high-fat, high sugar homemade diet ad libitum for seven weeks. The high-fat, high sugar diet included 59% of energy derived from fat, 30% from carbohydrates, and 11% from protein. Serum levels of fasting glucose, triglyceride, cholesterol, liver enzymes, insulin, and hepatic tumor necrosis factor-alpha (TNF-α) gene expression were determined. Hepatic histology was examined by H&E stain. RESULTS Rats fed the high-fat, high sugar diet developed hepatic steatosis, and a moderate inflammation, which was associated with increased serum levels of liver enzymes, glucose, insulin, triglyceride, cholesterol, and hepatic TNF-α gene expression. CONCLUSION This rat model resembles the key features of human NAFLD/NASH and provides a simple pragmatic experimental model for elucidating the disease prevention and treatment.
A human liver chimeric mouse model for non-alcoholic fatty liver disease
JHEP Reports, 2021
A human liver chimeric mouse model for non-alcoholic fatty liver disease Human Mouse TIRF mouse WD NAFLD human liver chimeric mouse Human liver chimeric mouse Metabolites Lipids Transcripts 12 weeks Humanization 8-12 weeks Hepatocyte isolation + transplantation Highlights Human liver chimeric mice fed a western diet develop NAFLD. Within the same chimeric liver, human hepatocytes developed pronounced steatosis while murine hepatocytes remained normal. Unbiased metabolomics and lipidomics of fatty humanised mouse livers revealed signatures of clinical NAFLD.