c-MYC overexpression in hepatocytes is associated with spontaneous development of non-alcoholic steatohepatitis (NASH) in mice

Background:

Non-alcoholic steatohepatitis (NASH) is a chronic liver disease associated with obesity, Diabetes mellitus type 2 (DM 2), and hyperlipidemia. It can also progress to irreversible liver cirrhosis and end-stage hepatocellular carcinoma (HCC); however, the underlying mechanism is still unknown, but endogenous (i.e. genetic) factors such as oncogenes have been suggested to play a role.

Aim:

Here we analysed the impact of the proto-oncogene c-MYC for the development of murine NASH.

Methods:

Transgenic mice bearing overexpression of c-MYC in hepatocytes (Alb-MYCtg) were studied for metabolic phenotype at baseline conditions (36 weeks). Serum markers of NASH were measured and hepatic steatosis, inflammation and fibrosis scored histologically.

Results:

Alb-MYCtgmice develop moderate degrees of obesity and significant increase in blood glucose after fasting, as well as after the glucose load, apparent in animals at 36 weeks. Moreover, Alb-MYCtg mice exhibit hypertriglyceridimia and hypercholesterolemia and profound hepatic changes at baseline, characterized by significant diffused microvesicular steatosis, hepatocellular ballooning and increased hepatic triglyceride content as compared to wildtype (WT) littermates. Liver injury and inflammation associated with elevated serum transaminases (e.g.:ALT), increased caspase-3 activity, upregulation of the ER-stress response genes (CHOP), marked infiltration of CD45 and F4/80 positive cells, mild perisinusoidal fibrogenic changes and compensatory proliferation.

Conclusions:

Alb-MYCtg-overexpressing mice develop mild obesity, glucose intolerance, hyperlipidemia and NASH in a middle age. The fact that 70% of transgenic mice develop HCC at the age of 70 weeks suggests an important role of the oncogene c-MYC during the progression from NASH to HCC.