Role of TWEAK in coregulating liver progenitor cell and fibrogenic responses

Tirnitz-Parker, Janina E.E., Olynyk, John K. and Ramm, Grant A. (2014) Role of TWEAK in coregulating liver progenitor cell and fibrogenic responses. Hepatology, 59 3: 1198-1201. doi:10.1002/hep.26701


Author Tirnitz-Parker, Janina E.E.
Olynyk, John K.
Ramm, Grant A.
Title Role of TWEAK in coregulating liver progenitor cell and fibrogenic responses
Journal name Hepatology   Check publisher's open access policy
ISSN 0270-9139
1527-3350
Publication date 2014-03
Year available 2014
Sub-type Article (original research)
DOI 10.1002/hep.26701
Open Access Status
Volume 59
Issue 3
Start page 1198
End page 1201
Total pages 4
Place of publication Hoboken, United States
Publisher John Wiley & Sons
Collection year 2015
Language eng
Formatted abstract
Failure of fibrotic liver to regenerate after resection limits therapeutic options and increases demand for liver transplantation, representing a significant clinical problem. The mechanism underlying regenerative failure in fibrosis is poorly understood. Seventy percent partial hepatectomy (PHx) was performed in C57Bl/6 mice with or without carbon tetrachloride (CCl4)-induced liver fibrosis. Liver function and regeneration was monitored at 1 to 14 days thereafter by assessing liver mass, alanine aminotransferase (ALT), mRNA expression, and histology. Progenitor (oval) cell mitogen tumor necrosis factor-like weak inducer of apoptosis (TWEAK) and TWEAK-neutralizing antibody were used to manipulate progenitor cell proliferation in vivo. In fibrotic liver, hepatocytes failed to replicate efficiently after PHx. Fibrotic livers showed late (day 5) peak of serum ALT (3542 ± 355 IU/L  compared to 93 ± 65 IU/L in nonfibrotic livers), which coincided with progenitor cell expansion, increase in profibrogenic gene expression and de novo collagen deposition. In fibrotic mice, inhibition of progenitor activation using TWEAK-neutralizing antibody after PHx resulted in strongly down-regulated profibrogenic mRNA, reduced serum ALT levels and improved  regeneration. Failure of hepatocyte-mediated regeneration in fibrotic liver triggers activation of the progenitor (oval) cell  compartment and a severe fibrogenic response. Inhibition of progenitor cell proliferation using anti-TWEAK antibody prevents fibrogenic response and augments fibrotic liver regeneration. Targeting the fibrogenic progenitor response represents a promising strategy to improve hepatectomy outcomes in patients with liver fibrosis.
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2015 Collection
School of Medicine Publications
 
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