Prevention of critical telomere shortening by oestradiol in human normal hepatic cultured cells and carbon tetrachloride induced rat liver fibrosis. Issue 7 (11th June 2004)

• Record Type: Journal Article
• Authors: Sato, R; Maesawa, C; Fujisawa, K; Wada, K; Oikawa, K; Takikawa, Y; Suzuki, K; Oikawa, H; Ishikawa, K; Masuda, T
• Is Part Of: Gut. Volume 53:Issue 7(2004)
• Page Start: 1001
• Page End: 1009
• Publication Date: 2004-06-11
• Subjects: 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; Gastroenterology -- Periodicals; 616.33
• DOI: 10.1136/gut.2003.027516
• Languages: English
• ISSNs: 0017-5749

Abstract

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.