title: Fibroblast growth factor signaling regulates the expansion of A6-expressing hepatocytes in association with AKT-dependent β-catenin activation.
abstract: OBJECTIVE
  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.
authors.affiliation: Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, CA 90027, USA; Integrative Biology of Diseases, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA.
authors.forename: Sarah
authors.initials: S
authors.lastname: Utley
authors.affiliation: Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, CA 90027, USA.
authors.forename: David
authors.initials: D
authors.lastname: James
authors.affiliation: Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, CA 90027, USA.
authors.forename: Nirmala
authors.initials: N
authors.lastname: Mavila
authors.affiliation: Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, CA 90027, USA.
authors.forename: Marie V
authors.initials: MV
authors.lastname: Nguyen
authors.affiliation: Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, CA 90027, USA.
authors.forename: Christopher
authors.initials: C
authors.lastname: Vendryes
authors.affiliation: Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, CA 90027, USA.
authors.forename: S Michael
authors.initials: SM
authors.lastname: Salisbury
authors.affiliation: Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, CA 90027, USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Phan
authors.affiliation: Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, CA 90027, USA. Electronic address: kwang@chla.usc.edu.
authors.forename: Kasper S
authors.initials: KS
authors.lastname: Wang
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D049109:Cell Proliferation; D056486:Chemical and Drug Induced Liver Injury / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051526:Fibroblast Growth Factor 10 / Q000235:genetics / Q000378:metabolism; D005346:Fibroblast Growth Factors / Q000235:genetics / Q000378:metabolism*; D056945:Hep G2 Cells; D051557:Hepatocyte Nuclear Factor 4 / Q000235:genetics / Q000378:metabolism; D022781:Hepatocytes / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008840:Microfilament Proteins / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D011725:Pyridines / Q000633:toxicity; D017468:Receptors, Fibroblast Growth Factor / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects; D051176:beta Catenin / Q000378:metabolism*
chemical_list: D015415:Biomarkers; D051526:Fibroblast Growth Factor 10; D005346:Fibroblast Growth Factors; D051557:Hepatocyte Nuclear Factor 4; D008840:Microfilament Proteins; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011505:Protein-Tyrosine Kinases; D051057:Proto-Oncogene Proteins c-akt; D011725:Pyridines; D017468:Receptors, Fibroblast Growth Factor; D051176:beta Catenin; C530773:3,5-diethoxycarbonyl-1,4-dihydrocollidine; C495267:CTNNB1 protein, mouse; C496464:Fgf10 protein, mouse; C496593:Hnf4a protein, mouse; C485188:TWF1 protein, human; C485190:Twf1 protein, mouse
keywords: Beta-catenin; DDC; Fibroblast growth factor 10; Hepatic progenitor cells