A Shortcut from Metabolic-Associated Fatty Liver Disease (MAFLD) to Hepatocellular Carcinoma (HCC): c-MYC a Promising Target for Preventative Strategies and Individualized Therapy

Simple Summary Metabolic-associated fatty liver disease (MAFLD) is a chronic liver disease associated with obesity, diabetes mellitus type 2 (DM2), and hyperlipidemia. It can also progress to end-stage hepatocellular carcinoma (HCC); the underlying mechanisms are still unknown, but endogenous (i.e., genetic) factors such as oncogenes have been suggested to play a role. We found that c-MYC transgenic mice with ageing are prone to develop obesity, metabolic syndrome (MS), and abnormal accumulation of lipids in the liver compared to control mice. A short-term application of the Western diet (WD) significantly worsened the phenotype and accelerate HCC development. Importantly, we found that metformin as therapeutic approach significantly attenuated MAFLD phenotype in transgenic mice. We also observed that c-MYC is up-regulated in human patients with MAFLD and MAFLD-related HCC. Altogether the current study suggests an important role of the oncogene c-MYC during the progression from MAFLD to HCC and makes c-MYC a possible target for preventative strategies and individualized therapy. Background: Metabolic-associated fatty liver disease (MAFLD) has risen as one of the leading etiologies for hepatocellular carcinoma (HCC). Oncogenes have been suggested to be responsible for the high risk of MAFLD-related HCC. We analyzed the impact of the proto-oncogene c-MYC in the development of human and murine MAFLD and MAFLD-associated HCC. Methods: alb-myc(tg) mice were studied at baseline conditions and after administration of Western diet (WD) in comparison to WT littermates. c-MYC expression was analyzed in biopsies of patients with MAFLD and MAFLD-associated HCC by immunohistochemistry. Results: Mild obesity, spontaneous hyperlipidaemia, glucose intolerance and insulin resistance were characteristic of 36-week-old alb-myc(tg) mice. Middle-aged alb-myc(tg) exhibited liver steatosis and increased triglyceride content. Liver injury and inflammation were associated with elevated ALT, an upregulation of ER-stress response and increased ROS production, collagen deposition and compensatory proliferation. At 52 weeks, 20% of transgenic mice developed HCC. WD feeding exacerbated metabolic abnormalities, steatohepatitis, fibrogenesis and tumor prevalence. Therapeutic use of metformin partly attenuated the spontaneous MAFLD phenotype of alb-myc(tg) mice. Importantly, upregulation and nuclear localization of c-MYC were characteristic of patients with MAFLD and MAFLD-related HCC. Conclusions: A novel function of c-MYC in MAFLD progression was identified opening new avenues for preventative strategies.