FGF receptors 1 and 2 control chemically induced injury and compound detoxification in regenerating livers of mice.
OBJECTIVE
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 tetrachloride-induced 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.
Böhm
Friederike
F
Department of Biology, Institute of Cell Biology, ETH Zürich, Switzerland.
Speicher
Tobias
T
Hellerbrand
Claus
C
Dickson
Clive
C
Partanen
Juha M
JM
Ornitz
David M
DM
Werner
Sabine
S
D000818:Animals; D050976:Basic-Leucine Zipper Transcription Factors / Q000235:genetics; D049109:Cell Proliferation; D002478:Cells, Cultured; D019610:Cytoprotection; D004268:DNA-Binding Proteins / Q000235:genetics; D006498:Hepatectomy; D022781:Hepatocytes / Q000502:physiology; D008658:Inactivation, Metabolic; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008115:Liver Regeneration; D008297:Male; D051379:Mice; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000502:physiology*; D051497:Receptor, Fibroblast Growth Factor, Type 2 / Q000502:physiology*; D014157:Transcription Factors / Q000235:genetics
D050976:Basic-Leucine Zipper Transcription Factors; D004268:DNA-Binding Proteins; C498260:Dbp protein, mouse; C489491:Tef protein, mouse; D014157:Transcription Factors; C496349:Fgfr1 protein, mouse; C496354:Fgfr2 protein, mouse; D051496:Receptor, Fibroblast Growth Factor, Type 1; D051497:Receptor, Fibroblast Growth Factor, Type 2