Background & Aims
Large liver cell changes (LLCC) are characterized by pleomorphic large nuclei frequently
found in liver diseases as chronic viral hepatitis and liver cirrhosis. The origin
of this lesion remains cryptic, but the presence of LLCC is correlated with an increased
risk of hepatocellular carcinoma. Telomeric repeat binding factor 1 (TRF1) is part
of the shelterin complex and is essential for telomere protection. Ablation of TRF1
induces telomere fragility and fusions and chromosomal instability.
Methods
In this study, we addressed the role of TRF1 in liver regeneration generating a mouse
model with conditional deletion of TRF1 in the liver.
Results
TRF1 deletion has no deleterious effects in liver and leads to increased ploidy of
hepatocytes after 2/3 hepatectomy. Mice lacking TRF1 in the liver can survive for
over one year without any evidence for altered liver function. Importantly, applying
chronic replicative stress by frequent carbon tetrachloride (CCl4) injections, TRF1 deleted mice undergo ploidy changes consistent with endoreduplication
and develop LLCC like lesions in the liver positive for p21, Cyclin D1 and PCNA as
observed in humans.
Conclusion
In summary, we provide mechanistic insight into the role of TRF1 in liver regeneration
and provide a mouse model recapitulating the clinical features of LLCC.
Abbreviations:
TRF1 and TRF2 (Telomeric repeat binding factors 1 and 2), TIN2 (tTRF1-interacting protein 2), POT1 (Protection of telomeres 1), TPP1 (POT1-TIN2 organizing protein), RAP1 (Repressor activator protein 1), LLCC (Large liver cell changes), SLCC (Small liver cell change), HCC (Hepatocellular carcinoma), DDR (DNA damage response), pI-pC (Polyinosinic-polycytidylic acid), CCl4 (Carbon tetrachloride), HE (Hematoxylin and eosin), IHC (immunohistochemistry), TIF (Telomere damage associated foci), Q-FISH (quantitative fluorescence in situ hybridization)Keywords
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Article info
Publication history
Published online: March 26, 2015
Accepted:
March 4,
2015
Received in revised form:
March 1,
2015
Received:
September 6,
2014
Identification
Copyright
© 2015 European Association for the Study of the Liver. Published by Elsevier Inc. All rights reserved.
