Article Text

PDF
Original article
ERK activation and autophagy impairment are central mediators of irinotecan-induced steatohepatitis
  1. Abdo Mahli1,2,
  2. Michael Saugspier1,
  3. Andreas Koch1,2,
  4. Judith Sommer1,2,
  5. Peter Dietrich2,
  6. Seren Lee3,
  7. Reinhard Thasler3,
  8. Jan Schulze-Luehrmann4,
  9. Anja Luehrmann4,
  10. Wolfgang Erwin Thasler3,
  11. Martina Müller1,
  12. Anja Bosserhoff2,5,
  13. Claus Hellerbrand1,2
  1. 1Department of Internal Medicine I, University Hospital Regensburg, Regensburg, Germany
  2. 2Institute of Biochemistry (Emil-Fischer Zentrum), Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany
  3. 3Biobank o.b. HTCR, Department of General Visceral- and Transplantation Surgery, Ludwig-Maximilians-University Munich, Munich, Germany
  4. 4Mikrobiologisches Institut – Klinische Mikrobiologie, Immunologie und Hygiene, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg, Erlangen, Germany
  5. 5Comprehensive Cancer Center Erlangen, CCC Erlangen-EMN, Erlangen, Germany
  1. Correspondence to Professor Claus Hellerbrand, Institute of Biochemistry, Friedrich-Alexander University Erlangen-Nürnberg, Erlangen D-91054, Germany; claus.hellerbrand{at}fau.de

Abstract

Objective 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.

Design 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.

Results 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.

Conclusions 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.

Statistics from Altmetric.com

Footnotes

  • Contributors AM, MS, AK, JS and PD performed the experiments. AM, JS-L, AL, AK and CH analysed the data. SL, RT, WET, MM and AKB provided material and performed Biobank search and analyses. AM and CH designed the project and wrote the manuscript.

  • Funding This work was supported by grants from the German Research Association (DFG) to AB and CH (FOR 2127; Bo1573 and He2458) and CH (KFO262; He2458) and by the Interdisciplinary Center for Clinical Research (IZKF) Erlangen to PD (J55) and AB (D24).

  • Competing interests None declared.

  • Ethics approval Tissue and Cell Research (HTCR) Foundation.

  • Provenance and peer review Not commissioned; externally peer reviewed.

Request permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.