Prevention of critical telomere shortening by oestradiol in human normal hepatic cultured cells and carbon tetrachloride induced rat liver fibrosis
Prevention of critical telomere shortening by oestradiol in human normal hepatic cultured cells and carbon tetrachloride induced rat liver fibrosis
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DOI：
10.1136/gut.2003.027516
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发表时间：
2004-07-01
期刊：
影响因子：
24.5
通讯作者：
Masuda, T
中科院分区：
文献类型：
--
作者：
Sato, R;Maesawa, C;Masuda, T
背景和目标：肝细胞的显著端粒缩短与慢性肝病中的复制性衰老和非分裂状态相关，导致终末期肝衰竭和/或肝细胞癌的发展。为了防止肝细胞中的关键端粒缩短，我们集中研究了雌激素依赖的人端粒酶逆转录酶（hTERT）基因的反式激活，作为慢性肝病中端粒酶治疗的一种形式。我们检测了三种人正常肝细胞系中hTERTmRNA及其蛋白的表达和端粒酶活性（HC细胞、h-Nhep和WRL-68）在用17 β-雌二醇处理之前和之后。在四氯化碳（CCl 4）诱导的大鼠肝纤维化模型中检测外源性雌二醇给药的影响。结果：雌二醇治疗可上调hTERTmRNA及其蛋白的表达。端粒长度减少HC-细胞和h-Nheps积累的通道，而长期雌二醇暴露，它是大于没有雌二醇。与未处理的细胞相比，雌二醇处理的细胞中β-半乳糖苷酶阳性细胞的发生率显著降低（p< 0.05），这表明细胞处于衰老状态。雌、雄大鼠肝纤维化模型中，雌、雄大鼠的TA在雌、雄雌雌激素干预后均显著高于对照组（P< 0.05）。长期给予雌二醇可显着挽救雄性和雌性大鼠肝脏端粒的广泛缩短。结论：这些结果表明雌二醇是肝脏hTERT基因的正向调节剂。雌激素依赖性hTERT基因的反式激活是减缓慢性肝病进展的新策略。
Background and aim: Significant telomere shortening of hepatocytes is associated with replicative senescence and a non-dividing state in chronic liver disease, resulting in end stage liver failure and/or development of hepatocellular carcinoma. To prevent critical telomere shortening in hepatocytes, we have focused on oestrogen dependent transactivation of the human telomerase reverse transcriptase ( hTERT) gene as a form of telomerase therapy in chronic liver disease.Methods: We examined expression of hTERT mRNA and its protein, and telomerase activity ( TA) in three human normal hepatic cell lines (Hc-cells, h-Nheps, and WRL-68) before and after treatment with 17beta-oestradiol. The effects of exogenous oestradiol administration were examined in a carbon tetrachloride (CCl4) induced model of liver fibrosis in rats.Results: Expression of hTERT mRNA and its protein was upregulated by oestradiol treatment. Telomere length decreased in Hc-cells and h-Nheps with accumulated passages whereas with long term oestradiol exposure it was greater than without oestradiol. The incidence of beta-galactosidase positive cells, indicating a state of senescence, decreased significantly in oestradiol treated cells in comparison with non-treated cells (p< 0.05). TA in both male and female rats with CCl4 induced liver fibrosis was significantly higher with oestradiol administration than without (p< 0.05). Long term oestradiol administration markedly rescued the hepatic telomere from extensive shortening in both male and female rats.Conclusion: These results suggest that oestradiol acts as a positive modulator of the hTERT gene in the liver. Oestrogen dependent transactivation of the hTERT gene is a new strategy for slowing the progression of chronic liver disease.