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Estrogen receptor β selective agonist ameliorates liver cirrhosis in rats by inhibiting the activation and proliferation of hepatic stellate cells
Author(s) -
Zhang Bin,
Zhang ChengGang,
Ji LinHua,
Zhao Gang,
Wu ZhiYong
Publication year - 2018
Publication title -
journal of gastroenterology and hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.214
H-Index - 130
eISSN - 1440-1746
pISSN - 0815-9319
DOI - 10.1111/jgh.13976
Subject(s) - hepatic stellate cell , agonist , medicine , endocrinology , ovariectomized rat , hepatic fibrosis , gper , estrogen receptor , antagonist , cirrhosis , estrogen , receptor , pharmacology , cancer , breast cancer
Abstract Background and Aim The 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). Methods Carbon tetrachloride (CCl 4 )‐induced cirrhotic ovariectomized rats were administered non‐selective ER agonist (β‐estradiol, E2), ER selective agonists (ERα agonist, propylpyrazoletriol; ERβ agonist, diarylpropionitrile [DPN]; and G‐protein‐coupled ER [GPER] agonist, G1), or E2 + ER selective antagonists (ERα antagonist, MPP; ERβ antagonist, PHTPP; and GPER antagonist, G15) for 12 weeks. 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. Results Selective ER agonists/antagonists had various effects on CCl 4 ‐induced cirrhosis. The cirrhotic rats in the CCl 4 + E2, CCl 4 + DPN, CCl 4 + E2 + MPP, and CCl 4 + E2 + G15 groups presented reduced fibrosis scores, compared with those in the CCl 4 group. The cirrhotic rats in the E2 + PHTPP group presented increased fibrosis scores that similar to those in the CCl 4 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 α‐smooth muscle actin expression. DPN also suppressed platelet‐derived growth factor‐induced proliferation in cultured HSCs, which was reversed by PHTPP. Conclusions The antifibrogenic effects of estrogen were mediated by ERβ but not ERα or GPER. The ERβ selective agonist exerted a fibrosuppressive effect by inhibiting the activation and proliferation of HSCs, but did not induce uterine hyperplasia.