title: Prevention of critical telomere shortening by oestradiol in human normal hepatic cultured cells and carbon tetrachloride induced rat liver fibrosis.
abstract: 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.
authors.affiliation: Department of Pathology, Iwate Medical University School of Medicine, 020-8505 Morioka, Japan.
authors.forename: R
authors.initials: R
authors.lastname: Sato
authors.forename: C
authors.initials: C
authors.lastname: Maesawa
authors.forename: K
authors.initials: K
authors.lastname: Fujisawa
authors.forename: K
authors.initials: K
authors.lastname: Wada
authors.forename: K
authors.initials: K
authors.lastname: Oikawa
authors.forename: Y
authors.initials: Y
authors.lastname: Takikawa
authors.forename: K
authors.initials: K
authors.lastname: Suzuki
authors.forename: H
authors.initials: H
authors.lastname: Oikawa
authors.forename: K
authors.initials: K
authors.lastname: Ishikawa
authors.forename: T
authors.initials: T
authors.lastname: Masuda
mesh_terms: 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
chemical_list: D004268:DNA-Binding Proteins; D047628:Estrogen Receptor alpha; D012333:RNA, Messenger; D011960:Receptors, Estrogen; D004958:Estradiol; D002251:Carbon Tetrachloride; D019098:Telomerase; D001616:beta-Galactosidase