Prevention of critical telomere shortening by oestradiol in human normal hepatic cultured cells and carbon tetrachloride induced rat liver fibrosis

Sato, R.; Maesawa, C.; Fujisawo, K.; Woda, K.; Oikawa, K.; Tokikawa, Y.; Suzuki, K.; Oikawa, H.; Ishikawa, K.; Masuda, T.
July 2004
Gut;Jul2004, Vol. 53 Issue 7, p1001
Academic Journal
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 17β-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 oesfradiol exposure it was greater than without oestradiol. The incidence of β-galactosidose 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 CCL 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.


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