Liver morphology and NAFLD progression in humans and zebrafish. (A) Zebrafish have a similar anatomy of the digestive system compared with humans. Tissue pathological processes can be studied for metabolic associated liver diseases. (B) The progression of NAFLD in humans and zebrafish. Lipid accumulation in the liver caused by obesity, insulin resistance and other factors leads to steatosis. Increased inflammation and oxidative stress promote NASH, and immune escape and fibrosis further lead to liver cirrhosis and even HCC. HCC, hepatocellular carcinoma; NAFLD, non-alcoholic fatty liver disease; NASH, non-alcoholic steatohepatitis.

Pathological mechanisms of NAFLD and main models in zebrafish. Possible pathological mechanisms of steatosis in NAFLD induced by diets, insulin resistance, pathogens and hepatoxic drugs, and the effects of mitochondrial dysfunction, endoplasmic reticulum stress and inflammatory cell infiltration which lead to inflammation, fibrosis and apoptosis in hepatocytes. The diet models, transgenic and mutation models involved are shown in the figure. ACC, acetyl-CoA carboxylase; CHOP, CCAAT/enhancer-binding protein homologous protein; CM, chylomicron; DAGs, diacylglycerols; DNL, de novo lipogenesis; EDCs, endocrine-disrupting chemicals; ER, endoplasmic reticulum; FFA, free fatty acid; FAS, fatty acid synthase; FXR, farnesoid X receptor; HBV, hepatitis B virus; HSC, hepatic stellate cell; JAK-STAT, Janus kinase/signal transducer and activator of transcription; JUNK, Jun amino-terminal kinase; LPCs, lysophosphatidylcholines; LXR, liver X receptors; MO, morpholino; mTOR, mechanistic target of rapamycin; PPAR, peroxisome proliferators-activated receptors; ROS, reactive oxygen species; SCD, stearoyl-CoA desaturase; SREBP-1C, sterol regulatory element binding protein 1c; TG, triglyceride; UPR, unfolded protein response; VLDL, very low-density lipoprotein.

Applications of zebrafish NAFLD models. Zebrafish models facilitate the research of NAFLD in revealing the roles of specific genes and pathways in NAFLD progression, evaluating the hepatoxicity of drugs and exogenous chemicals, and identifying novel therapeutic compounds for NAFLD. EDCs, endocrine-disrupting chemicals; HCD, high-cholesterol diet; HFD, high-fat diet; NAFLD, non-alcoholic fatty liver disease.