Fibroblast growth factor signaling regulates the expansion of A6-expressing hepatocytes in association with AKT-dependent ß-catenin activation.
J Hepatol
; 60(5): 1002-9, 2014 May.
Article
em En
| MEDLINE
| ID: mdl-24365171
ABSTRACT
BACKGROUND & AIMS:
Fibroblast Growth Factors (FGFs) promote the proliferation and survival of hepatic progenitor cells (HPCs) via AKT-dependent ß-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 ß-catenin signaling. Herein, we investigate the role of FGF signaling and AKT-mediated ß-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) ß-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-ß-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 ß-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 ß-Catenin expansion of A6(+ive) periportal cells and possibly by reprogramming of centrolobular hepatocytes.Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Hepatócitos
/
Proteínas Proto-Oncogênicas c-akt
/
Beta Catenina
/
Fatores de Crescimento de Fibroblastos
/
Proteínas dos Microfilamentos
Tipo de estudo:
Risk_factors_studies
Limite:
Animals
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Humans
/
Male
Idioma:
En
Ano de publicação:
2014
Tipo de documento:
Article