Fatty liver, one of the most common liver diseases, is often caused by excessive intake
of high- calorie food. The course of the disease ranges from simple hepatic steatosis
to an inflammatory reaction to liver fibrosis and cirrhosis. Both, patients with and
without cirrhosis have an enhanced risk to develop a hepatocellular carcinoma.
For the study of liver disease progression under high-calorie diet, wt and Par4 knock-out
mice were fed with western diet for up to 50 weeks.
In the longitudinal analysis of the progression of fatty liver disease wt mice show
a significant increase the concentration of the serum parameter AST, ALT and LDH,
especially after 16 and/or 26 weeks. After 30 weeks, there was a significant increase
in RNA expression of TGFb1, 2, and 3 and increased collagen formation in liver tissue,
accompanied by increased expression of various chemokines and the formation of so-called
crown-like structures mainly from recruited macrophages. After 40 weeks of feeding,
25% and after 50 weeks of feeding, 60% of the animals developed macroscopically visible
liver tumors. In comparison, the Par4 knock-out animals showed significantly reduced
concentrations of AST, ALT, and LDH during the course of feeding, and fibrosis of
the liver is significantly reduced. In addition, no PAR4 knock-out animal showed tumors
after 50 weeks and only 1 animal had developed a tumor after 40 weeks of feeding.
In comparision to the wt mice, the depletion of Par4 appears to lead to a reduction
in liver injury induced by a high-calorie diet.
