title: ERK activation and autophagy impairment are central mediators of irinotecan-induced steatohepatitis.
abstract: Preoperative chemotherapy with irinotecan is associated with the development of steatohepatitis, which increases the risk of perioperative morbidity and mortality for liver surgery. The molecular mechanisms of this chemotherapeutic complication are widely unknown.
  
  
  
  Mechanisms of irinotecan-induced steatohepatitis were studied in primary human hepatocytes in vitro, in mice treated with irinotecan and in liver specimens from irinotecan-treated compared with control patients.
  
  
  
  Irinotecan dose-dependently induced lipid accumulation and pro-inflammatory gene expression in hepatocytes. This was accompanied by an impairment of mitochondrial function with reduced expression of carnitine palmitoyltransferase I and an induction of acyl-coenzyme A oxidase-1 (ACOX1), oxidative stress and extracellular signal-regulated kinase (ERK) activation. ERK inhibition prevented irinotecan-induced pro-inflammatory gene expression but had only a slight effect on lipid accumulation. However, irinotecan also induced an impairment of the autophagic flux mediated by alkalisation of lysosomal pH. Re-acidification of lysosomal pH abolished irinotecan-induced autophagy impairment and lipid accumulation. Also in mice, irinotecan treatment induced hepatic ACOX1 expression, ERK phosphorylation and inflammation, as well as impairment of autophagy and significant steatosis. Furthermore, irinotecan-treated patients revealed higher hepatic ERK activity, expression of pro-inflammatory genes and markers indicative for a shift to peroxisomal fatty acid oxidation and an impaired autophagic flux. Pretreatment with the multityrosine kinase inhibitor sorafenib did not affect autophagy impairment and steatosis but significantly reduced ERK phosphorylation and inflammatory response in irinotecan-treated hepatocytes and murine livers.
  
  
  
  Irinotecan induces hepatic steatosis via autophagy impairment and inflammation via ERK activation. Sorafenib appears as a novel therapeutic option for the prevention and treatment of irinotecan-induced inflammation.
authors.affiliation: Department of Internal Medicine I, University Hospital Regensburg, Regensburg, Germany.|Institute of Biochemistry (Emil-Fischer Zentrum), Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany.
authors.forename: Abdo
authors.initials: A
authors.lastname: Mahli
authors.affiliation: Department of Internal Medicine I, University Hospital Regensburg, Regensburg, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Saugspier
authors.affiliation: Department of Internal Medicine I, University Hospital Regensburg, Regensburg, Germany.|Institute of Biochemistry (Emil-Fischer Zentrum), Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Koch
authors.affiliation: Department of Internal Medicine I, University Hospital Regensburg, Regensburg, Germany.|Institute of Biochemistry (Emil-Fischer Zentrum), Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany.
authors.forename: Judith
authors.initials: J
authors.lastname: Sommer
authors.affiliation: Institute of Biochemistry (Emil-Fischer Zentrum), Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Dietrich
authors.affiliation: Biobank o.b. HTCR, Department of General Visceral- and Transplantation Surgery, Ludwig-Maximilians-University Munich, Munich, Germany.
authors.forename: Seren
authors.initials: S
authors.lastname: Lee
authors.affiliation: Biobank o.b. HTCR, Department of General Visceral- and Transplantation Surgery, Ludwig-Maximilians-University Munich, Munich, Germany.
authors.forename: Reinhard
authors.initials: R
authors.lastname: Thasler
authors.affiliation: Mikrobiologisches Institut - Klinische Mikrobiologie, Immunologie und Hygiene, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg, Erlangen, Germany.
authors.forename: Jan
authors.initials: J
authors.lastname: Schulze-Luehrmann
authors.affiliation: Mikrobiologisches Institut - Klinische Mikrobiologie, Immunologie und Hygiene, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg, Erlangen, Germany.
authors.forename: Anja
authors.initials: A
authors.lastname: Luehrmann
authors.affiliation: Biobank o.b. HTCR, Department of General Visceral- and Transplantation Surgery, Ludwig-Maximilians-University Munich, Munich, Germany.
authors.forename: Wolfgang Erwin
authors.initials: WE
authors.lastname: Thasler
authors.affiliation: Department of Internal Medicine I, University Hospital Regensburg, Regensburg, Germany.
authors.forename: Martina
authors.initials: M
authors.lastname: Müller
authors.affiliation: Institute of Biochemistry (Emil-Fischer Zentrum), Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany.|Comprehensive Cancer Center Erlangen, CCC Erlangen-EMN, Erlangen, Germany.
authors.forename: Anja
authors.initials: A
authors.lastname: Bosserhoff
authors.affiliation: Department of Internal Medicine I, University Hospital Regensburg, Regensburg, Germany.|Institute of Biochemistry (Emil-Fischer Zentrum), Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany.
authors.forename: Claus
authors.initials: C
authors.lastname: Hellerbrand
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000009:adverse effects*; D001343:Autophagy / Q000187:drug effects*; D002166:Camptothecin / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives*; D004195:Disease Models, Animal; D005234:Fatty Liver / Q000139:chemically induced*; D022781:Hepatocytes / Q000187:drug effects*; D006801:Humans; D066298:In Vitro Techniques; D000077146:Irinotecan; D008113:Liver Neoplasms / Q000188:drug therapy; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D051379:Mice; D008810:Mice, Inbred C57BL; D011300:Preoperative Care / Q000009:adverse effects*
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D000077146:Irinotecan; D002166:Camptothecin
keywords: LIVER; LIVER METASTASES; PHARMACOTHERAPY; SURGICAL ONCOLOGY