FGF receptors 1 and 2 control chemically induced injury and compound detoxification in regenerating livers of mice

Friederike Böhm, Tobias Speicher, Claus Hellerbrand, Clive Dickson, Juha M. Partanen, David M. Ornitz, Sabine Werner

Research output: Contribution to journalArticlepeer-review

38 Scopus citations

Abstract

Background & Aims Fibroblast growth factor receptor 4 (FGFR4) controls bile acid metabolism and protects the liver from fibrosis, but the roles of FGFR1 and FGFR2 in the adult liver are largely unknown. We investigated the functions and mechanisms of action of these receptors in liver homeostasis, regeneration, and fibrosis. Methods We generated mice with hepatocytes that lack FGFR1 and FGFR2 and subjected them to acute and chronic carbon tetrachlorideinduced liver injury and partial hepatectomy; mice were also injected with FGF7. We performed histology, histomorphometry, real-time reverse transcription polymerase chain reaction, and immunoblot analyses. Results In hepatocytes, loss of FGFR1 and FGFR2 eliminated responsiveness to FGF7 and related FGF family members but did not affect toxin-induced liver injury and fibrosis. However, mortality after partial hepatectomy increased because of severe hepatocyte necrosis. These effects appeared to be mediated by a failure of hepatocytes to induce the expression of the transcriptional regulators Dbp and Tef upon liver surgery; this affected expression of their target genes, which encode detoxifying cytochrome P450 enzymes. We found that Dbp and Tef expression was directly controlled by FGFR signaling in hepatocytes. As a consequence of the reduced expression of genes that control detoxification, the liver tissue that remained after partial hepatectomy failed to efficiently metabolize endogenous compounds and the drugs applied for anesthesia/analgesia. Conclusions We identified a new, cytoprotective effect of FGFR1 and FGFR2 in the regenerating liver and suggest the use of recombinant FGF7 to increase survival of patients after surgical resection of large amounts of liver tissue.

Original languageEnglish
Pages (from-to)1385-1396.e8
JournalGastroenterology
Volume139
Issue number4
DOIs
StatePublished - Oct 2010

Keywords

  • Cirrhosis
  • Cytoprotection
  • Drug Toxicity
  • Liver Disease

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