Aim: Estradiol treatment regulates estrogen receptor (ER) level in normal rat liver. However, little information is available concerning the role of estrogen in regulating liver ER in hepatic fibrosis in rats. The present study was conducted to determine whether estradiol treatment in CCl4-induced liver fibrosis of female and ovariectomized rats altered liver ERalpha and its mRNA expression, and to investigate the possible mechanisms.
Methods: Seventy female rats were divided into seven groups with ten rats in each. The ovariectomy groups were initiated with ovariectomies and the sham operation groups were initiated with just sham operations. The CCl4 toxic fibrosis groups received 400 mL/L CCl4 subcutaneously at a dose of 2 mL/kg twice weekly. Estrogen groups were treated subcutaneously with estradiol 1 mg/kg, the normal control group and an ovariectomy group received injection of peanut oil vehicle twice weekly. At the end of 8 weeks, all the rats were killed to detect their serum and hepatic indicators, their hepatic collagen content, and liver ER and ER mRNA expression.
Results: Estradiol treatment in both ovariectomy and sham ovariectomy groups reduced liver levels of ALT (from 658 +/- 220 nkat/L to 311 +/- 146 nkat/L and 540 +/- 252 nkat/L to 314 +/- 163 nkat/L, P<0.05) and AST (from 697 +/- 240 nkat/L to 321 +/- 121 nkat/L and 631 +/- 268 nkat/L to 302 +/- 153 nkat/L, P<0.05), increased serum nitric oxide (NO) level (from 53.7 +/- 17.1 micromol/L to 93.3 +/- 24.2 micromol/L and 55.3 +/- 23.1 micromol/L to 87.5 +/- 23.6 micromol/L, P<0.05) and hepatic nitric oxide synthase (NOS) activity (from 1.73 +/- 0.71 KU/g to 2.49 +/- 1.20 KU/g and 1.65 +/- 0.46 KU/g to 2.68 +/- 1.17 KU/g, P<0.05), diminished the accumulation of hepatic collagen, decreased centrolobular necrotic areas as well as the inflammatory reaction in rats subjected to CCl4. The positive signal of ER and ER mRNA distributed in parenchymal and non-parenchymal hepatic cells, especially near the hepatic centrolobular and periportal areas. Ovariectomy decreased ER level (from 10.2 +/- 3.2 to 4.3 +/- 1.3) and ER mRNA expression (from 12.8 +/- 2.1 to 10.9 +/- 1.3) significantly (P<0.05). Hepatic ER and ER mRNA concentrations were elevated after treatment with estradiol in both ovariectomy (15.8 +/- 2.4, 20.8 +/- 3.1) and sham ovariectomy (18.7 +/- 3.8, 23.1 +/- 3.7) fibrotic groups (P<0.05).
Conclusion: The increase in hepatic ER and mRNA expression may be part of the molecular mechanisms underlying the suppressive effect of estradiol on liver fibrosis induced by CCl4 administration.