title: Analysis of molecular mechanisms of 5-fluorouracil-induced steatosis and inflammation in vitro and in mice.
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 β-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.affiliation: Institute of Biochemistry (Emil-Fischer-Zentrum), Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany.|Department of Internal Medicine I, University Hospital Regensburg, Germany.
authors.forename: Judith
authors.initials: J
authors.lastname: Sommer
authors.affiliation: Institute of Biochemistry (Emil-Fischer-Zentrum), Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany.|Department of Internal Medicine I, University Hospital Regensburg, Germany.
authors.forename: Abdo
authors.initials: A
authors.lastname: Mahli
authors.affiliation: Institute of Biochemistry (Emil-Fischer-Zentrum), Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany.|Department of Internal Medicine I, University Hospital Regensburg, Germany.
authors.forename: Kim
authors.initials: K
authors.lastname: Freese
authors.affiliation: Biobank o.b. HTCR, Department of General Visceral- and Transplantation Surgery, Ludwig-Maximilians-University Munich, Munich, Germany.
authors.forename: Tobias S
authors.initials: TS
authors.lastname: Schiergens
authors.affiliation: Department of Internal Medicine I, University Hospital Regensburg, Germany.
authors.forename: Fulya Suzan
authors.initials: FS
authors.lastname: Kuecuekoktay
authors.affiliation: Department of Internal Medicine I, University Hospital Regensburg, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Teufel
authors.affiliation: Biobank o.b. HTCR, Department of General Visceral- and Transplantation Surgery, Ludwig-Maximilians-University Munich, Munich, Germany.
authors.forename: Wolfgang E
authors.initials: WE
authors.lastname: Thasler
authors.affiliation: Department of Internal Medicine I, University Hospital Regensburg, Germany.
authors.forename: Martina
authors.initials: M
authors.lastname: Müller
authors.affiliation: Institute of Biochemistry (Emil-Fischer-Zentrum), Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany.|Comprehensive Cancer Center Erlangen, CCC Erlangen-EMN; Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany.
authors.forename: Anja K
authors.initials: AK
authors.lastname: Bosserhoff
authors.affiliation: Institute of Biochemistry (Emil-Fischer-Zentrum), Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany.|Department of Internal Medicine I, University Hospital Regensburg, Germany.
authors.forename: Claus
authors.initials: C
authors.lastname: Hellerbrand
mesh_terms: D042962:Acyl-CoA Oxidase / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology / Q000633:toxicity; D015153:Blotting, Western; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004789:Enzyme Activation / Q000187:drug effects; D005234:Fatty Liver / Q000139:chemically induced / Q000235:genetics* / Q000378:metabolism; D005260:Female; D005472:Fluorouracil / Q000494:pharmacology* / Q000633:toxicity; D015870:Gene Expression / Q000187:drug effects; D051547:Heme Oxygenase-1 / Q000235:genetics / Q000378:metabolism; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000139:chemically induced / Q000235:genetics* / Q000378:metabolism; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism; D016209:Interleukin-8 / Q000235:genetics / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D008810:Mice, Inbred C57BL; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014280:Triglycerides / Q000378:metabolism
chemical_list: D000964:Antimetabolites, Antineoplastic; D016209:Interleukin-8; D014280:Triglycerides; D018799:Intercellular Adhesion Molecule-1; C496541:HMOX1 protein, human; D051547:Heme Oxygenase-1; D042962:Acyl-CoA Oxidase; D048031:JNK Mitogen-Activated Protein Kinases; D005472:Fluorouracil
keywords: 5-FU; mitochondrial dysfunction; steatohepatitis; steatosis