Telomere and Telomerase Group, Molecular Oncology Program, Spanish National Cancer Research Centre (CNIO), Madrid, Spain; Department of Hematology, Oncology and Stem Cell Transplantation, University of Aachen, Aachen, Germany.
Telomere and Telomerase Group, Molecular Oncology Program, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
J Hepatol. 2015 Aug;63(2):446-55. doi: 10.1016/j.jhep.2015.03.022. Epub 2015 Mar 27.
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.
In this study, we addressed the role of TRF1 in liver regeneration generating a mouse model with conditional deletion of TRF1 in the liver.
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.
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.
大肝细胞改变（LLCC）的特征是多形性大核，常存在于慢性病毒性肝炎和肝硬化等肝脏疾病中。这种病变的起源仍然不清楚，但 LLCC 的存在与肝细胞癌的风险增加有关。端粒重复结合因子 1（TRF1）是庇护体复合物的一部分，对于端粒保护至关重要。TRF1 的缺失会导致端粒脆弱、融合和染色体不稳定。
在这项研究中，我们通过在肝脏中建立条件性缺失 TRF1 的小鼠模型，研究了 TRF1 在肝再生中的作用。
TRF1 缺失对肝脏没有不良影响，并在 2/3 肝切除后导致肝细胞的多倍体增加。肝脏中缺失 TRF1 的小鼠可以存活一年以上，而没有任何肝功能改变的证据。重要的是，通过频繁的四氯化碳（CCl4）注射施加慢性复制应激，缺失 TRF1 的小鼠会发生与内复制一致的倍性变化，并在肝脏中出现类似于人类的 LLCC 样病变，这些病变呈 p21、Cyclin D1 和 PCNA 阳性。
总之，我们提供了 TRF1 在肝再生中的作用的机制见解，并提供了一个能够重现 LLCC 临床特征的小鼠模型。
