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.
