Background: Non-alcoholic fatty liver disease (NAFLD) is increasing at an alarming rate due, in part to the rising incidence of obesity worldwide. A proportion of patients with NAFLD will progress to the more seious liver disease termed non-alcoholic steatohepatitis (NASH), which is a risk factor for the development of hepatocellular carcinoma (HCC) (1). Bland hepatosteatosis, the first stage of NASH progression, is excessive accumulation of hepatic triglycerides, major mechanisms of which include enhanced de novo lipogenesis (DNL) and impaired β oxidation(2). In an effort to treat metabolic disorders including NASH, we generated a chimeric cytokine, IC7Fc, which decreased lipogenesis in the liver and increased fatty acids oxidation via activation of AMPK, and improved metabolic homeostasis in mice (3). Accordingly, we tested the hypothesis that IC7Fc could be a potential treatment for NASH.
Methods: MuP-uPA transgenic mice have been shown to be a useful animal model to mimic human NASH progression(4). Male MuP-uPA mice were randomly divided into IC7Fc-treated group (n=12) and Fc control-treated group (n=12). All the mice were fed high fat diet (HFD) from 6 to 23 weeks of age. During this diet intervention, mice underwent intraperitoneal injection of IC7Fc (1mg/kg) or Fc control weekly and body weight and body composition were monitored via magnetic resonance imaging. Liver tissues were obtained for H&E staining from liver biopsy surgery and their endpoint at 12 weeks and 23 weeks of age, respectively.
Results: IC7Fc significantly improved liver steatosis and inflammation infiltration (P<0.05) when compared with Fc control-treated mice. Importantly, treatment of IC7Fc attenuated NASH progression (Total NAFLD activity score P<0.05 between IC7Fc and Fc groups). In addition, IC7Fc decreased body weight and fat body mass (P<0.05), and maintained lean body mass.
Conclusion: As an AMPK activator, IC7Fc reduces liver steatosis and attenuates NASH progression. Treatment of IC7Fc improves body composition and metabolic homeostasis in mice.