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


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 oestradiol exposure it was greater than without oestradiol. The incidence of β-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.

  • HSC, hepatic stellate cells
  • TGF-β1, transforming growth factor-β1
  • M1, mortality stage 1
  • M2, mortality stage 2
  • OR, oestrogen receptor
  • TA, telomerase activity
  • TRF, terminal restriction fragment
  • RQ-PCR, real time quantitative-polymerase chain reaction
  • TRE assay, telomeric repeat elongation assay
  • e value, elongation value
  • CCl4, carbon tetrachloride
  • SDS, sodium dodecyl sulphate
  • RU, resonance unit
  • PBS, phosphate buffered saline
  • telomerase
  • telomerase reverse transcriptase
  • chronic liver disease
  • oestrogen receptor
  • telomeric repeat elongation assay

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