Non-Alcoholic Fatty Liver Disease: Translating Disease Mechanisms into Therapeutics Using Animal Models

Abstract

Nonalcoholic fatty liver disease (NAFLD) is a range of pathologies arising from fat accumulation in the liver in the absence of excess alcohol use or other causes of liver disease. Its complications include cirrhosis and liver failure, hepatocellular carcinoma, and eventual death. NAFLD is the most common cause of liver disease globally and is estimated to affect nearly one-third of individuals in the United States. Despite knowledge that the incidence and prevalence of NAFLD are increasing, the pathophysiology of the disease and its progression to cirrhosis remain insufficiently understood. The molecular pathogenesis of NAFLD involves insulin resistance, inflammation, oxidative stress, and endoplasmic reticulum stress. Better insight into these molecular pathways would allow for therapies that target specific stages of NAFLD. Preclinical animal models have aided in defining these mechanisms and have served as platforms for screening and testing of potential therapeutic approaches. In this review, we will discuss the cellular and molecular mechanisms thought to contribute to NAFLD, with a focus on the role of animal models in elucidating these mechanisms and in developing therapies.

Keywords: ER stress; animal models; fatty liver; metabolism; nutrition.

Figure 1

Pathogenesis of NAFLD. Insulin resistance stimulates the breakdown of adipose triglycerides into free fatty acids (FFA) that enter the liver and accumulate there as triglycerides. Excess dietary sugars are converted into additional triglycerides via de novo lipogenesis. Pro-inflammatory cytokines from the adipose tissue and lipopolysaccharides (LPS) from the gastrointestinal tract contribute directly or indirectly to hepatic inflammation. Cholesterol accumulates in the liver due to impaired very-low-density lipoprotein (VLDL) secretion and bile formation, as well as increased de novo biosynthesis of cholesterol. These cellular insults trigger the mitochondria to produce toxic levels of reactive oxygen species (ROS). Additionally, cellular insults activate endoplasmic reticulum (ER) stress and the unfolded protein response. Together, these pathways upregulate pro-inflammatory cytokine expression (IFNγ, TNFα, and IL-6), apoptotic mediators (CHOP and JNK), and immune-response mediators (NFκB and NLRP3). Ultimately, this results in hepatic inflammation and cell death, leading to NASH and fibrosis. Image created with Biorender.com.