Question Non-alcoholic fatty liver disease is a condition characterized by excess
of
fat in liver ranging from simple steatosis to steatohepatitis, cirrhosis, and
hepatocellular carcinoma (HCC). In our study, we aimed to investigate the relevance
of ferroptosis for disease progression using hepatocyte-specific ACSL4 deletion in
an experimental HCC model.
Methods Primary hepatocytes from either wild-type mice or mice with
hepatocyte-specific deletion of ACSL4 (ACSL4Δhepa) were treated with
specific inducers (e.g., RSL3) and inhibitors (e.g., Liproxstatin-1) of ferroptosis.
We used STZ (Streptozocin) with high-fat diet as HCC model, where different time
points of disease progression were studied to investigate the role of
ferroptosis.
Results Treatment of primary hepatocytes with RSL3 triggered increased ferroptotic
cell death, which could be rescued by Liproxstatin-1 or by ACSL4 deletion. At the
stage of tumor initiation in our HCC model, inhibition of ferroptosis in hepatocytes
increases the severity of chronic liver disease as evidenced by elevated serum
transaminase levels in ACSL4Δhepa mice. Importantly, the overall tumor
burden was increased, too. Interestingly, ACSL4 deletion does not significantly
affect inflammation. However, enhanced oxidative stress and remarkably decreased
ferroptotic and apoptotic cell death was observed in ACSL4Δhepa mice.
Moreover, evaluation of HCC progression at later stage showed no effect on overall
tumor burden but significantly reduced proliferation in ACSL4Δhepa mice.
Conclusion Our results demonstrate that primary mouse hepatocytes are susceptible
to
ferroptosis induction and that it depends on functional ACSL4. In vivo in our HCC
model, ACSL4 deletion increases tumor initiation, but has no significant impact on
tumor progression.
Lecture Session V Viral Hepatitis and Immunology
29/01/2022, 11.00 am – 11.45 am, Lecture Hall
