NAFLD模型揭示加速细胞衰老的特征，如再生障碍，和肝癌的风险增加。NAFLD肝细胞加速衰老、疾病的进展和临床转归之间的关系还未被研究，这是当前研究的主题。采用定量荧光原位杂交和免疫组化的方法分别对70例非酒精性脂肪肝患者（105活检）和60名对照者在肝细胞端粒长度、核面积、DNA损伤和细胞周期阶段标记方面进行研究。NAFID患者的肝细胞端粒短于对照组(p<0.0001)。已被证明，NAFLD肝细胞缺乏细胞周期的G1 / S期、高表达p21，普遍的细胞周期抑制剂（P = 0.001）。预示着DNA的损伤的Y-H(2)AX的表达能增加细胞脂肪变性(p=0.01) ，并且和肝细胞端粒缩短相关(p <0.0001)。肝细胞p21基因表达与肝纤维化分期和糖尿病相关(p <0.001, p=0.002, 分别的). 进一步研究发现，肝脏相关不良转归与肝细胞p21的高表达和肝细胞核面积增大（P = 0.02，P=0.006）关系紧密，但与端粒长度无相关性。在成对的肝脏活检中，肝细胞p21的表达和核面积的改变反映了肝纤维化分期变化（P = 0.01，P=0.006）。这些研究结果与NAFLD患者的肝细胞衰老和永久性细胞周期阻滞相一致。肝细胞衰老与肝脏纤维化分期、糖尿病、临床转归密切相关。肝细胞p21的表达可以作为临床研究分层中的预后指标。
吉林大学第一医院肝病科 刘永方 摘译
本文首次发表于[J Hepatol,2013,58(3):549-556]
Hepatocyte senescence predicts progression in non-alcohol-related fatty liver disease
Abstract
BACKGROUND & AIMS:
Models of non-alcohol-related fatty liver disease (NAFLD) reveal features of accelerated ageing, such as impaired regeneration, and an increased risk of hepatocellular carcinoma. The relation between accelerated ageing, disease progression and clinical outcome has not been previously investigated and is the subject of the current study.
METHODS:
Liver sections from 70 patients with NAFLD (105 biopsies) and 60 controls were studied for telomere length, nuclear area, DNA damage and cell cycle phase markers, using quantitative fluorescent in situ hybridization and immunohistochemistry.
RESULTS:
Hepatocyte telomeres were shorter in NAFLD than controls (p <0.0001). Hepatocytes in NAFLD demonstrated lack of cell cycleprogression beyond G1/S phase and high-level expression of p21, the universal cell cycle inhibitor (p=0.001). γ-H(2)AX expression increased with steatosis (p=0.01), indicating DNA damage, and was associated with shorter hepatocyte telomeres (p <0.0001). Hepatocyte p21 expression correlated with fibrosis stage and diabetes mellitus, independently (p <0.001 and p=0.002, respectively). Further analysis revealed that an adverseliver-related outcome was strongly associated with higher hepatocyte p21 expression and greater hepatocyte nuclear area (p=0.02 and p=0.006), but not with telomere length. In paired biopsies, changes in hepatocyte p21 expression and nuclear area mirrored changes in fibrosis stage (p=0.01 and p=0.006, respectively).
CONCLUSIONS:
These findings are consistent with hepatocyte senescence and permanent cell cycle arrest in NAFLD. Hepatocyte senescencecorrelated closely with fibrosis stage, diabetes mellitus, and clinical outcome. Hepatocyte p21 expression could be used as a prognostic marker and for stratification in clinical studies.
