1. Background
Non-alcoholic fatty liver disease (NAFLD) and alcoholic liver disease (ALD) refer to a disease spectrum, ranging from mere hepatic steatosis to hepatic necroinflammation. According to statistics, about 30% of the general adult population and 70–80% of diabetic and obese patients are affected by NAFLD and ALD1, which is several- fold higher than hepatitis C and alcohol-related liver disease. Long-term consumption of excessive alcoholic often results in ALD. NASH (non-alcoholic steatohepatitis) and ASH (alcoholic steatohepatitis) normally lead to fibrosis, which can progress to cirrhosis with a high risk of liver failure and hepatocellular carcinoma2-3. However, the mechanism of the progression from NASH/ASH to steatohepatitis and fibrosis is still not fully understood.
The farnesoid X receptor (FXR) is a member of the nuclear receptor superfamily, which mainly expresses in liver, intestine, kidney and adrenal gland at the tissue level.4 It functions as a bile acid (BA) sensor coordinating cholesterol metabolism, lipid homeostasis, and absorption of dietary fats and vitamins5. According to the previous researches, FXR plays a very critical role in maintaining hepatic lipid and bile acid homeostasis. Severe liver injury and steatohepatitis were observed in Lieber-DeCarli ethanol diet treated FXR-/- mice, compared with steatosis and rare inflammation on wildtypes3. FXR agonist WAY-362450 protected mice from the development of ALD induced by Lieber-DeCarli ethanol diet. In addition, WAY-362450 treatment rescued FXR activity, suppressed ethanol-induced Cyp2e1 up-regulation and attenuated oxidative stress in liver.6 These results demonstrate the key role of FXR in the development of ASH.
However, most research focused on non-alcoholic fatty liver disease, using FXR-null mice with high fat diet to create the model of NAFLD mice.7-11 The study of alcoholic steatohepatitis are still limited, especially on the tissue specific-FXR knock out mice. Thus, attention should be paid more on the research of ASH.
2. Objective
Based on the research to find out the roles of FXR in ASH development, it is very promising to find out a new target for curing alcoholic fatty liver disease.
3. Research Plan
3.1 Material:
3.1.1 Animals:
C57BL/6 Mice, all male
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