| First Author | Utley S | Year | 2014 |
| Journal | J Hepatol | Volume | 60 |
| Issue | 5 | Pages | 1002-9 |
| PubMed ID | 24365171 | Mgi Jnum | J:357941 |
| Mgi Id | MGI:6839469 | Doi | 10.1016/j.jhep.2013.12.017 |
| Citation | Utley S, et al. (2014) Fibroblast growth factor signaling regulates the expansion of A6-expressing hepatocytes in association with AKT-dependent beta-catenin activation. J Hepatol 60(5):1002-9 |
| abstractText | BACKGROUND & AIMS: Fibroblast Growth Factors (FGFs) promote the proliferation and survival of hepatic progenitor cells (HPCs) via AKT-dependent beta-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 beta-catenin signaling. Herein, we investigate the role of FGF signaling and AKT-mediated beta-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) beta-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-beta-Catenin((positive)+ive) periportal cells as well as cells co-positive for A6 and hepatocyte marker, Hepatocyte Nuclear Factor-4alpha (HNF4alpha). 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)HNF4alpha(+ive) cell population while reducing centrolobular A6(+ive) HNF4alpha(+ive) cells. AKT inhibition with Wortmannin attenuated FGF10-mediated A6(+ive)HNF4alpha(+ive) cell expansion. In vitro analyses using FGF10 treated HepG2 cells demonstrated AKT-mediated beta-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 beta-Catenin expansion of A6(+ive) periportal cells and possibly by reprogramming of centrolobular hepatocytes. |
