A study for replicative senescence in hepatocytes in hepatic fibrosis

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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 hepatocytes from critical telomere shortening, we are focusing on an estrogen-dependent transactivation of human telomerase reverse transcriptase (hTERT) gene as a telomerase therapy in chronic liver disease. We examined hTERTmRNA and protein expressions, and telomerase activity (TA) in 3 human normal hepatic cell lines (Hc-cells, h-Nheps and WRL-68) before and after treatment with 17β-estradiol (E2). The hTERT mRNA and protein expressions were up-regulated in Hc-cells and h-Nheps by E_2-treatment, while overexpression of hTERT gene was observed in WRL-68 even before the treatment. Telomere length decreased with accumulated passages in Hc-cells and h-Nheps, whereas that with long-term E_2 exposure was longer than that without E_2. Incidence of β-galactosidase positive cells, indicating senescence state, significantly decreased in E_2-treated cells in comparison with non-treated cells (P<.05). Effects of exogenous E_2 administration on TA and telomere length were examined in CCl4-induced liver fibrosis model of rats. TA of both male and female rats of CCl4-induced liver fibrosis with E_2 administration significantly higher than those without E_2 administration (P<.05). Gender-related difference in TA was not observed. Long-term E_2 administration could drastically rescue the hepatic telomere from extensive shortening in both male and female rats. These results suggest that estradiol acts as a positive-modulator of hTERT gene in the liver and may prolong the lifespan of hepatocytes by the prevention of extensive telomere shortening. The estrogen-dependent transactivation of the hTERT gene is a new strategy for slowing the progression of chronic liver disease.