Z Gastroenterol 2020; 58(01): e45-e46
DOI: 10.1055/s-0039-3402223
Poster Visit Session IV Tumors: Saturday, February 15, 2020, 8:30 am – 09:15 am, Lecture Hall P1
Georg Thieme Verlag KG Stuttgart · New York

The role of ferroptosis in chronic liver disease

J Piche
1   University Hospital RWTH Aachen, Department of Internal Medicine III, Aachen, Germany
,
T Otto
1   University Hospital RWTH Aachen, Department of Internal Medicine III, Aachen, Germany
,
A Mohs
1   University Hospital RWTH Aachen, Department of Internal Medicine III, Aachen, Germany
,
MM Woitok
1   University Hospital RWTH Aachen, Department of Internal Medicine III, Aachen, Germany
,
C Trautwein
1   University Hospital RWTH Aachen, Department of Internal Medicine III, Aachen, Germany
› Author Affiliations
Further Information

Publication History

Publication Date:
03 January 2020 (online)

 

Question:

The prevalence of non-alcoholic fatty liver disease, ranging from steatosis to non-alcoholic steatohepatitis (NASH), is increasing in developed countries. In some patients, progression towards cirrhosis and hepatocellular carcinoma (HCC) occurs. To present, the underlying mechanisms for disease progression remain incompletely understood. In NASH oxidative stress and lipid peroxidation constitute prominent features and may hence play a key role. Interestingly, accumulation of lipid peroxides can trigger ferroptosis, an iron-dependent mode of cell death. According to in vitro studies, acyl-CoA synthetase long-chain family member 4 (ACSL4) is an essential contributor to ferroptosis. In our study, we aimed to investigate the relevance of ferroptosis for disease progression using hepatocyte-specific ACSL4 inhibition in experimental models of chronic liver disease.

Methods:Primary hepatocytes from either wild-type (WT) 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. In addition, we compared disease development between WT and ACSL4Δhepa mice to investigate the role of ferroptosis. We used a high-fat diet (HFD) to trigger NASH and STZ (Streptozocin) with HFD as a NASH-HCC model.

Results:

Treatment of primary hepatocytes with RSL3 leads to increased cell death, which could be rescued by adding Liproxstatin-1 or by using ACSL4-deficient hepatocytes.

In our HFD-based NASH model, we did not find significant differences between WT and ACSL4Δhepa mice. Specifically, liver-to-body weight ratio, serum transaminase levels, and immune cell infiltration were not altered. In contrast, in our NASH-HCC model, inhibition of ferroptosis in hepatocytes augments chronic liver disease resulting in increased serum transaminase levels in ACSL4Δhepa mice. Importantly, while the overall tumor burden was not affected in ACSL4Δhepa mice, the number of smaller tumors was significantly increased.

Conclusion:

Our results demonstrate that primary mouse hepatocytes are susceptible to induction of ferroptosis and that this mode of cell death depends on functional ACSL4. Interestingly, ferroptosis seems to be a protective mechanism during tumor initiation, by regulating lipid accumulation and cell death in hepatocytes. Therefore, activation of ferroptosis or inhibiting key molecules regulating cell death, can be a possible therapeutic treatment for human disease.