Table 1.
Comparison of rodent models of alcohol-associated liver disease.
| Rodent Models | Feeding Mode | Pathological Features | Advantages and Disadvantages | References |
|---|---|---|---|---|
| Model Using Alcohol Alone | ||||
| Lieber–DeCarli model | Chronic ethanol feeding (4–12 weeks) | ALT and AST levels were elevated, and it caused a certain degree of liver damage but rarely caused liver inflammation. | Easy to perform mild steatosis Short-term feeding with no mortality rate |
[12,13,111,114] |
| Tsukamoto–French model | Intragastric infusion (2–3 months) | ALT levels were significantly elevated, and it led to severe steatosis, fibrosis, and cirrhosis with focal necrosis and immune cell infiltration. | Difficult to perform the requirement for intensive medical care Long-term feeding with a high mortality rate |
[117,118,119,120,121,122,123,124] |
| The chronic plus binge model | LDE diet plus a single binge or multiple binges |
ALT and AST levels were significantly elevated, it caused fatty liver and inflammation as well as neutrophil infiltration, and aged mice were more susceptible to liver damage and inflammation. | Easy to perform Short-term (10 d) feeding with no mortality rate Long-term feeding plus multiple binges with a high mortality rate |
[11,101,115,125,126,127,128] |
| Second Hit Models | ||||
| HFD plus ethanol | 3dHFD plus ethanol or 3mHFD plus ethanol |
ALT and AST levels increased obviously, it induced acute hepatitis and injury, and it increased the infiltration of liver neutrophils and reduced liver macrophages. | This model needs a longer modelling period Simulates acute steatohepatitis in obese alcoholics |
[18,129,130] |
| Iron carbonyl plus ethanol | Ethanol plus iron carbonyl (0.12% w/v for the first week, 0.25% w/v for the second week and beyond, for 16 weeks) | ALT and AST levels increased obviously, and it resulted in moderate to severe fatty liver as well as central necrosis and inflammation of the liver lobules, liver fibrosis, and even cirrhosis. | Time-consuming and costly Overcomes the animals’ natural aversion to ethanol Showed most of the disease course and liver pathology of ALD |
[118] |
| LPS plus ethanol | Alcohol gavage (6 g/kg bw) plus LPS (10 mg/kg bw) | The levels of ALT and AST were significantly increased, increasing the degree of necrosis and hepatic neutrophil infiltration. | Easy to perform severe steatosis and inflammation | [16,131,132] |
| LDE diet for 4 weeks, 5% ethanol w/v gavage plus intraperitoneal injection of LPS (2 mg/kg) | Liver sections also showed lipid droplet accumulation and enhanced liver damage, with distinct areas of necrosis and inflammatory cell infiltration. Moreover, the levels of ALT were significantly increased. | |||
| CCl4 plus ethanol | LDE diet plus CCl4 injection (0.5 μL/kg, once every 3 days for 8 weeks) | This resulted in an exacerbation of hepatic fibrosis, characterized by increased activation of HSC. | Easy to perform liver fibrosis Toxic components Long-term model showed most of the disease course and liver pathology of ALD, but it was time-consuming |
[17,133,134,135,136,137] |
| Inhaling CCl4 plus ethanol for 7 wk (4% in the first week, 8% in the second week, and 16% afterwards) | It caused significant fibrosis within 4 weeks and strong proinflammatory reaction. | |||
| Intraperitoneal injection of CCl4 (0.2% mL/kg for 28 weeks) combined with LDE diet (containing 5% v/v ethanol for 10 weeks) | It caused hepatic steatosis, inflammation, fibrosis, hepatocyte swelling, and tumour nodules in mice. | |||
| APAP plus ethanol | APAP (300 mg/kg bw) plus ethanol 4 g/kg every 12 h × 5 doses or three weekly ethanol binges | Significantly elevated ALT and AST levels, causing infiltration of erythrocytes in the space of Disse at 2 h after APAP treatment. | Displayed severe hepatotoxicity and early ALD features in the short term | [138] |
| DEN plus ethanol | LDE diet plus DEN (75 mg/kg for first three weeks and 100 mg/kg for the next three weeks) | Liver damage continued to increase and eventually showed increased recruitment of precancerous liver macrophages with mixed M1/M2 phenotype. | Reflected alcohol-induced HCC in terms of histology and genetics | [139,140] |
| DEN10 (mg/kg) was injected intraperitoneally in 2-week-old mice and LDE diet (4.8% alcohol for 3–7 weeks) was given at 3 months of age | Alcohol intake significantly increased the number of surface tumours in mice. | Visible superficial tumours were induced and serum alpha-fetoprotein levels increased to 3 times the normal level | ||