Analysis of molecular mechanisms of 5-fluorouracil-induced steatosis and inflammation in vitro and in mice

Sommer J, Mahli A, Freese K, Schiergens TS, Kuecuekoktay FS, Teufel A, Thasler WE, Mueller M, Boßerhoff AK, Hellerbrand C (2017)

Publication Type: Journal article

Publication year: 2017

Journal

Oncotarget Impact Journals

Book Volume: 8

Pages Range: 13059-13072

Journal Issue: 8

DOI: 10.18632/oncotarget.14371

Abstract

Chemotherapy-associated steatohepatitis is attracting increasing attention because it heralds an increased risk of morbidity and mortality in patients undergoing surgery because of liver metastases. The aim of this study was to develop in vitro and in vivo models to analyze the pathogenesis of 5-fluorouracil (5-FU)-induced steatohepatitis.Therefore, primary human hepatocytes and HepG2 hepatoma cells were incubated with 5-FU at non-toxic concentrations up to 24 h. Furthermore, hepatic tissue of C57BL/6N mice was analyzed 24 h after application of a single 5-FU dose (200 mg/kg body weight). In vitro, incubation with 5-FU induced a significant increase of hepatocellular triglyceride levels. This was paralleled by an impairment of mitochondrial function and a dose- and time-dependently increased expression of fatty acid acyl-CoA oxidase 1 (ACOX1), which catalyzes the initial step for peroxisomal ?-oxidation. The latter is known to generate reactive oxygen species, and consequently, expression of the antioxidant enzyme heme oxygenase 1 (HMOX1) was significantly upregulated in 5-FU-treated cells, indicative for oxidative stress. Furthermore, 5-FU significantly induced c-Jun N-terminal kinase (JNK) activation and the expression of pro-inflammatory genes IL-8 and ICAM-1. Also in vivo, 5-FU significantly induced hepatic ACOX1 and HMOX1 expression as well as JNK-activation, pro-inflammatory gene expression and immune cell infiltration. In summary, we identified molecular mechanisms by which 5-FU induces hepatocellular lipid accumulation and inflammation. Our newly developed models can be used to gain further insight into the pathogenesis of 5-FU-induced steatohepatitis and to develop therapeutic strategies to inhibit its development and progression.

Authors with CRIS profile

Judith Sommer Lehrstuhl für Biochemie und Molekulare Medizin Abdo Mahli Lehrstuhl für Biochemie und Molekulare Medizin Kim Freese Lehrstuhl für Biochemie und Molekulare Medizin Anja Katrin Boßerhoff Lehrstuhl für Biochemie und Molekulare Medizin Claus Hellerbrand Professur für Biochemie und Molekulare Pathobiologie

Involved external institutions

Ludwig-Maximilians-Universität (LMU) DE Germany (DE) Universitätsklinikum Regensburg DE Germany (DE)

How to cite

APA:

Sommer, J., Mahli, A., Freese, K., Schiergens, T.S., Kuecuekoktay, F.S., Teufel, A.,... Hellerbrand, C. (2017). Analysis of molecular mechanisms of 5-fluorouracil-induced steatosis and inflammation in vitro and in mice. Oncotarget, 8(8), 13059-13072. https://dx.doi.org/10.18632/oncotarget.14371

MLA:

Sommer, Judith, et al. "Analysis of molecular mechanisms of 5-fluorouracil-induced steatosis and inflammation in vitro and in mice." Oncotarget 8.8 (2017): 13059-13072.

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