Fibroblast growth factor signaling regulates the expansion of A6-expressing hepatocytes in association with AKT-dependent β-catenin activation

J Hepatol. 2014 May;60(5):1002-9. doi: 10.1016/j.jhep.2013.12.017. Epub 2013 Dec 21.

Abstract

Background & aims: Fibroblast Growth Factors (FGFs) promote the proliferation and survival of hepatic progenitor cells (HPCs) via AKT-dependent β-catenin activation. Moreover, the emergence of hepatocytes expressing the HPC marker A6 during 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC)-induced liver injury is mediated partly by FGF and β-catenin signaling. Herein, we investigate the role of FGF signaling and AKT-mediated β-catenin activation in acute DDC liver injury.

Methods: Transgenic mice were fed DDC chow for 14days concurrent with either Fgf10 over-expression or inhibition of FGF signaling via expression of soluble dominant-negative FGF Receptor (R)-2IIIb.

Results: After 14days of DDC treatment, there was an increase in periportal cells expressing FGFR1, FGFR2, and AKT-activated phospho-Serine 552 (pSer552) β-Catenin in association with up-regulation of genes encoding the FGFR2IIIb ligands, Fgf7, Fgf10, and Fgf22. In response to Fgf10 over-expression, there was an increase in the number of pSer552-β-Catenin((positive)+ive) periportal cells as well as cells co-positive for A6 and hepatocyte marker, Hepatocyte Nuclear Factor-4α (HNF4α). A similar expansion of A6(+ive) cells was observed after Fgf10 over-expression with regular chow and after partial hepatectomy during ethanol toxicity. Inhibition of FGF signaling increased the periportal A6(+ive)HNF4α(+ive) cell population while reducing centrolobular A6(+ive) HNF4α(+ive) cells. AKT inhibition with Wortmannin attenuated FGF10-mediated A6(+ive)HNF4α(+ive) cell expansion. In vitro analyses using FGF10 treated HepG2 cells demonstrated AKT-mediated β-Catenin activation but not enhanced cell migration.

Conclusions: During acute DDC treatment, FGF signaling promotes the expansion of A6-expressing liver cells partly via AKT-dependent activation of β-Catenin expansion of A6(+ive) periportal cells and possibly by reprogramming of centrolobular hepatocytes.

Keywords: Beta-catenin; DDC; Fibroblast growth factor 10; Hepatic progenitor cells.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Biomarkers / metabolism
  • Cell Proliferation
  • Chemical and Drug Induced Liver Injury / genetics
  • Chemical and Drug Induced Liver Injury / metabolism
  • Chemical and Drug Induced Liver Injury / pathology
  • Fibroblast Growth Factor 10 / genetics
  • Fibroblast Growth Factor 10 / metabolism
  • Fibroblast Growth Factors / genetics
  • Fibroblast Growth Factors / metabolism*
  • Hep G2 Cells
  • Hepatocyte Nuclear Factor 4 / genetics
  • Hepatocyte Nuclear Factor 4 / metabolism
  • Hepatocytes / cytology*
  • Hepatocytes / drug effects
  • Hepatocytes / metabolism*
  • Humans
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Microfilament Proteins / metabolism*
  • Phosphoinositide-3 Kinase Inhibitors
  • Protein-Tyrosine Kinases / metabolism
  • Proto-Oncogene Proteins c-akt / metabolism*
  • Pyridines / toxicity
  • Receptors, Fibroblast Growth Factor / genetics
  • Receptors, Fibroblast Growth Factor / metabolism
  • Signal Transduction / drug effects
  • Stem Cells / cytology
  • Stem Cells / metabolism
  • Up-Regulation / drug effects
  • beta Catenin / metabolism*

Substances

  • 3,5-diethoxycarbonyl-1,4-dihydrocollidine
  • Biomarkers
  • CTNNB1 protein, mouse
  • Fgf10 protein, mouse
  • Fibroblast Growth Factor 10
  • Hepatocyte Nuclear Factor 4
  • Hnf4a protein, mouse
  • Microfilament Proteins
  • Phosphoinositide-3 Kinase Inhibitors
  • Pyridines
  • Receptors, Fibroblast Growth Factor
  • TWF1 protein, human
  • Twf1 protein, mouse
  • beta Catenin
  • Fibroblast Growth Factors
  • Protein-Tyrosine Kinases
  • Proto-Oncogene Proteins c-akt