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Prevention of critical telomere shortening by oestradiol in human normal hepatic cultured cells and carbon tetrachloride induced rat liver fibrosis
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  1. R Sato1,
  2. C Maesawa1,
  3. K Fujisawa1,
  4. K Wada1,
  5. K Oikawa1,
  6. Y Takikawa2,
  7. K Suzuki2,
  8. H Oikawa1,
  9. K Ishikawa3,
  10. T Masuda1
  1. 1Department of Pathology, Iwate Medical University School of Medicine, 020-8505 Morioka, Japan
  2. 2First Department of Internal Medicine, Iwate Medical University School of Medicine, 020-8505 Morioka, Japan
  3. 3Department of Nursing, Iwate Prefectural University, 152-52 Sugo, Takizawa-mura, Iwate-gun, 020-0173, Iwate, Japan
  1. Correspondence to:
    Dr C Maesawa
    Department of Pathology, Iwate Medical University School of Medicine, Uchimaru 19-1, 020-8505 Morioka, Japan; chihayaiwate-med.ac.jp

Abstract

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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