Antioxidant-based therapy in non-alcoholic steatohepatitis (NASH) and NASH-induced hepatocellular carcinoma development

Life-style alterations such as high caloric intake combined with a sedentary lifestyle have highly augmented over the last decades the number of obese people in Western Countries, and it's expected to increase further in the near future. Non-alcoholic fatty liver disease (NAFLD) represents the most common liver morbidity, characterized by excessive fat accumulation (steatosis). Around 30% of patients having NAFLD, develop non-alcoholic steatohepatitis (NASH) that shows beyond steatosis, also chronic inflammation, hepatocellular damage and fibrosis. The pathogenic condition of NASH constitutes a major risk factor for hepatocellular carcinoma (HCC), the most common primary liver malignancy and the third most common cause worldwide of cancer-related death. To date, the exact mechanism underlying NASH and NASH-induced HCC is still unknown. In the context of NASH, high caloric diet leads to oxidative stress originated by the increased levels of radical oxygen species (ROS) produced mainly by endogenous aberrant mitochondria, endoplasmic reticulum (ER) and peroxisomes. The final effect of overproduction of ROS is the enhancement of lipid peroxidation and protein oxidation, thus leading to a detrimental effect in the homeostasis of fatty acids in the liver and to ER stress. Especially the lipid peroxidation is considered a relevant source of mutagens triggered by ROS. Persistent oxidative stress modifies lipids, proteins and DNA; while it also leads to a deregulated immune response and increased proliferation, eventually favoring tumorigenesis. This is relevant not only in livers of NASH affected patients but also in HCC cases. To study the role of ROS in NASH and in NASH-induced HCC mouse models, we tested in combination with choline-deficient high-fat diet (CDHFD), a xanthophyll carotenoid compound. Our aim was to assess whether therapeutic treatment with an antioxidant in the presence of NASH CDHFD-induced, would ameliorate the NASH phenotype and reduce cancer incidence. The prophylactic treatment led to a lower NAFLD activity score. In addition, it decreased significantly hepatic inflammation and proliferation. The therapeutic treatment instead, reduced the cancer incidence. Our data indicate that oxidative stress is indeed an important driver of tumorigenesis that should be considered in NASH therapeutic practice in order to reduce cancer risk.