Estrogen receptor selective agonist ameliorates liver cirrhosis in rats by inhibiting the activation and proliferation of hepatic stellate cells

Background and AimThe aim of this study is to explore the roles of estrogen receptor (ER) subtypes and corresponding agonists/antagonists on the development of cirrhosis and activation and proliferation of hepatic stellate cells (HSCs). MethodsCarbon tetrachloride (CCl4)-induced cirrhotic ovariectomized rats were administered non-selective ER agonist (-estradiol, E2), ER selective agonists (ER agonist, propylpyrazoletriol; ER agonist, diarylpropionitrile [DPN]; and G-protein-coupled ER [GPER] agonist, G1), or E2+ER selective antagonists (ER antagonist, MPP; ER antagonist, PHTPP; and GPER antagonist, G15) for 12weeks. The expression of the three ER subtypes in livers and HSCs and the effects of the drugs on hepatic fibrosis, isolated HSCs, and uteri were evaluated. ResultsSelective ER agonists/antagonists had various effects on CCl4-induced cirrhosis. The cirrhotic rats in the CCl4+E2, CCl4+DPN, CCl4+E2+MPP, and CCl4+E2+G15 groups presented reduced fibrosis scores, compared with those in the CCl4 group. The cirrhotic rats in the E2+PHTPP group presented increased fibrosis scores that similar to those in the CCl4 group. The ovariectomized rats had enlarged uteri with increased uterus indexes after E2 administration; however, the proliferative effects of E2 were partially blocked by MPP or G15, but not PHTPP. In the in vitro study, DPN attenuated the transformation of quiescent HSCs to activated phenotype, suppressed collagen I, and -smooth muscle actin expression. DPN also suppressed platelet-derived growth factor-induced proliferation in cultured HSCs, which was reversed by PHTPP. ConclusionsThe antifibrogenic effects of estrogen were mediated by ER but not ER or GPER. The ER selective agonist exerted a fibrosuppressive effect by inhibiting the activation and proliferation of HSCs, but did not induce uterine hyperplasia.