Prevention of critical telomere shortening by oestradiol in human normal hepatic cultured cells and carbon tetrachloride induced rat liver fibrosis.
OBJECTIVE
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 17beta-oestradiol. The effects of exogenous oestradiol administration were examined in a carbon tetrachloride (CCl(4)) 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 beta-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 CCl(4) 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.


CONCLUSIONS
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.
Sato
R
R
Department of Pathology, Iwate Medical University School of Medicine, 020-8505 Morioka, Japan.
Maesawa
C
C
Fujisawa
K
K
Wada
K
K
Oikawa
K
K
Takikawa
Y
Y
Suzuki
K
K
Oikawa
H
H
Ishikawa
K
K
Masuda
T
T
D000818:Animals; D002251:Carbon Tetrachloride; D002460:Cell Line; D016922:Cellular Senescence / Q000187:drug effects*; D004268:DNA-Binding Proteins; D004958:Estradiol / Q000494:pharmacology*; D047628:Estrogen Receptor alpha; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D008106:Liver Cirrhosis, Experimental / Q000139:chemically induced / Q000235:genetics / Q000473:pathology*; D008297:Male; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D011916:Rats, Inbred F344; D011960:Receptors, Estrogen / Q000378:metabolism; D019098:Telomerase / Q000235:genetics / Q000378:metabolism; D016615:Telomere / Q000187:drug effects*; D001616:beta-Galactosidase / Q000378:metabolism
D004268:DNA-Binding Proteins; D047628:Estrogen Receptor alpha; D012333:RNA, Messenger; D011960:Receptors, Estrogen; D004958:Estradiol; D002251:Carbon Tetrachloride; D019098:Telomerase; D001616:beta-Galactosidase