Non-alcoholic fatty liver disease: pathogenesis and models

Abstract

Non-alcoholic fatty liver disease (NAFLD) is a complex disease characterized by a massive accumulation of lipids in the liver, with a continuous progression of simple steatosis, non-alcoholic steatohepatitis (NASH), cirrhosis, and hepatocellular carcinoma. Non-alcoholic fatty liver disease is associated with obesity, insulin resistance, and metabolic syndrome; it is a severe public health risk and is currently the most common liver disease of the world. In addition to the fatty infiltration of the liver in non-alcoholic fatty liver disease patients, the field of liver transplantation faces similar obstacles. NAFLD and NASH primarily involve lipotoxicity, inflammation, oxidative stress, and insulin resistance. However, the precise mechanisms and treatments remain unclear. Therapeutic approaches encompass exercise, weight control, as well as treatments targeting antioxidants and anti-inflammatory pathways. The role of animal models in research has become crucial as a key tool to explore the molecular mechanisms and potential treatments for non-alcoholic fatty liver disease and non-alcoholic steatohepatitis. Here, we summarized the current understanding of the pathogenesis of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis and discussed animal models commonly used in recent years.

Keywords: animal models; histopathology; non-alcoholic fatty liver disease (NAFLD); non-alcoholic steatohepatitis (NASH); pathogenesis; treatment.

Figure 1

Mechanisms underlying non-alcoholic fatty liver disease (NAFLD) include adipose tissue (AT) dysfunction, obesity, increased hepatic free fatty acids (FFAs) levels, impaired β-oxidation, and insulin resistance. AT dysfunction leads to low adiponectin and high leptin levels, leading to hepatic insulin resistance and increased lipolysis. Increased lipolysis in the adipose tissue and excessive consumption of fats in the diet lead to increased free fatty acids in the liver. Hepatic insulin resistance leads to increased de novo lipogenesis and increasing triglyceride levels. The main pathways for the treatment of steatosis include weight control, activation of the AMPK and the inhibition of the SREBP-1c. AT, adipose tissue; DNL, de novo lipogenesis; FFAs, free fatty acids; IR, insulin resistance; TG, triglycerides; AMPK, AMP-activated protein kinase.

Figure 2

In non-alcoholic steatohepatitis (NASH), the mechanisms include reactive oxygen species (ROS) and inflammation. The increase in free fatty acids (FFA) delivered to the liver leads to lipotoxic molecules and mitochondrial β-oxidation. The main pathways for the treatment of NASH include weight control, activation of the AMPK, antioxidant medications and inhibition of relevant inflammatory pathways, such as c-JNK, IκKβ. AT, adipose tissue; DNL AT, adipose tissue; c-JNK, c-Jun NH2-terminal kinase; FFAs, free fatty acids; IκKβ, inhibitor of nuclear factor kappa-B kinase subunit beta; IL-6, interleukin 6; IR, insulin resistance; NASH, non-alcoholic steatohepatitis; ROS, reactive oxygen species; TNF-α, tumor necrosis factor alpha; AMPK, AMP-activated protein kinase; NF-κB, Nuclear Factor Kappa B.