Pathophysiological Features of Rat Models of Nonalcoholic Fatty Liver Disease/Nonalcoholic Steatohepatitis

Abstract

Nonalcoholic fatty liver disease (NAFLD)/ nonalcoholic steatohepatitis (NASH) is caused by various factors, including genetic and/or environmental factors, and has complicated pathophysiological features during the development of the disease. NAFLD/NASH is recognized as an unmet medical need, and NAFLD/NASH animal models are essential tools for developing new therapies, including potential drugs and biomarkers. In this review, we describe the pathological features of the NAFLD/NASH rat models, focusing on the histopathology of hepatic fibrosis. NAFLD/NASH rat models are divided into three categories: diet-induced, genetic, and combined models based on diet, chemicals, and genetics. Rat models of NASH with hepatic fibrosis are especially expected to contribute to the development of new therapies, such as drugs and biomarkers.The liver is the largest organ in the human body and performs various functions to maintain human health. Hepatic abnormalities in fatty liver disease include steatosis and steatosis-related liver damage. There are two types of fatty liver disease: alcoholic and nonalcoholic. Alcoholic fatty liver disease is caused by heavy alcohol consumption. However, the factors and mechanisms involved in the development of nonalcoholic fatty liver disease (NAFLD) are not fully understood. If not managed, both types of fatty liver disease progress to cirrhosis and liver cancer via hepatitis. NAFLD is a common liver disease worldwide with an alarmingly rapid prevalence (1-3). NAFLD is histopathologically classified as nonalcoholic fatty liver (NAFL) and nonalcoholic steatohepatitis (NASH). NASH is a severe condition characterized by necroinflammation that progresses to cirrhosis and liver cancer. Animal models of NAFLD/NASH are pivotal in developing novel NAFLD/NASH therapies. The US Food and Drug Administration has provided guidance for the development of new drugs for the treatment of non-cirrhotic NASH with liver fibrosis, with no worsening of steatohepatitis and liver fibrosis as endpoints in clinical trials (https://www.fda.gov/media/119044/download). It is necessary to develop NAFLD/NASH models of hepatic inflammation/ fibrosis and to understand the pathophysiological features of these models. NAFLD/NASH models can be divided into three categories: genetic, dietary, and chemical. In this review, we focus on dietary and genetic rat models that exhibit hepatic pathological features. We also describe the pathological changes in the combined models based on genetics, diet, and chemicals. Diet-induced NAFLD/NASH Rat ModelsWestern diets and amino acid-modified diets are widely used to induce NAFLD/NASH-like lesions. Normal rats, such as Sprague-Dawley (SD) and Wistar rats, develop NAFLD/ NASH-like changes, including steatosis, inflammation, and fibrosis, chiefly caused by western-style diets. Fischer 344 (F344) rats also develop NASH-like lesions following a choline-deficient, methionine-lowered, L-amino acid-defined (CDAA) diet. Pathological characteristics of diet-induced NAFLD/NASH rat models are summariz...