Journal
JOURNAL OF HEPATOLOGY
Volume 60, Issue 5, Pages 1002-1009Publisher
ELSEVIER SCIENCE BV
DOI: 10.1016/j.jhep.2013.12.017
Keywords
Fibroblast growth factor 10; Hepatic progenitor cells; DDC; Betacatenin
Categories
Funding
- National Institutes of Health [K08 AAA01690]
- Franklin Martin Award
- American College of Surgeons
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Background & Aims: Fibroblast Growth Factors (FGFs) promote the proliferation and survival of hepatic progenitor cells (HPCs) via AKT-dependent b-catenin activation. Moreover, the emergence of hepatocytes expressing the HPC marker A6 during 3,5diethoxycarbonyl- 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 14 days concurrent with either Fgf10 over-expression or inhibition of FGF signaling via expression of soluble dominant-negative FGF Receptor (R)-2IIIb. Results: After 14 days 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-4 alpha (HNF4 alpha). 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)HNF4 alpha+ ive cell population while reducing centrolobular A6+ ive HNF4 alpha(+ive) cells. AKT inhibition with Wortmannin attenuated FGF10-mediated A6(+ive)HNF4 alpha+ 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 A(6+ive) periportal cells and possibly by reprogramming of centrolobular hepatocytes. (c) 2013 European Association for the Study of the Liver. Published by Elsevier B. V. All rights reserved.
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