Background and Aim:Sulfotransferase(SULT)-mediated sulfation and steroid sulfatase(STS)-mediated desulfation represent two critical mechanisms that regulate the chemical and functional homeostasis of endogenous and ex...Background and Aim:Sulfotransferase(SULT)-mediated sulfation and steroid sulfatase(STS)-mediated desulfation represent two critical mechanisms that regulate the chemical and functional homeostasis of endogenous and exogenous molecules.STS catalyzes the hydrolysis of steroid sulfates to form hydroxysteroids.Oxygenated cholesterol derivative oxysterols are known to be endogenous ligands of the liver X receptor(LXR),a nuclear receptor with anti-cholestasis activity,whereas the sulfated oxysterols antagonize LXR signaling.The conversion of sulfated oxysterols to their non-sulfated counterparts is catalyzed by STS.The aim of this study is to determine whether STS can alleviate cholestasis by increasing the activity of LXR.Methods:Liver-specific STS transgenic mice were created and subject to the lithocholic acid(LCA)-induced model of cholestasis.Results:Transgenic overexpression of STS in the liver promoted bile acid elimination and alleviated LCAinduced cholestasis.The protective effect of the STS transgene was associated with the activation of LXR and induction of LXR target genes,likely because of the increased conversion of the antagonistic oxysterol sulfates to the agonistic oxysterols.Conclusions:STS has a novel function in controlling the homeostasis of bile acids by regulating endogenous LXR ligands.展开更多
In post-menopausal women,intra-mammary estrogen,which is converted from extra-ovarian estrone(E1),promotes the growth of breast cancer.Since the aromatase inhibitor letrozole does not suppress 17β-estradiol(E2)produc...In post-menopausal women,intra-mammary estrogen,which is converted from extra-ovarian estrone(E1),promotes the growth of breast cancer.Since the aromatase inhibitor letrozole does not suppress 17β-estradiol(E2)production from E1,high intra-mammary E1 concentrations impair letrozole's therapeutic efficacy.Progesterone receptor membrane component 1(Pgrmc1)is a non-classical progesterone receptor associated with breast cancer progression.In the present study,we introduced a Pgrmc1 heterozygous knockout(hetero KO)murine model exhibiting low Pgrmc1 expression,and observed estrogen levels and steroidogenic gene expression.Naïve Pgrmc1 hetero KO mice exhibited low estrogen(E2 and E1)levels and low progesterone receptor(PR)expression,compared to wild-type mice.In contrast,Pgrmc1 hetero KO mice that have been ovariectomized(OVX),including letrozole-treated OVX mice(OVX-letrozole),exhibited high estrogen levels and PR expression.Increased extra-ovarian estrogen production in Pgrmc1 hetero KO mice was observed with the induction of steroid sulfatase(STS).In MCF-7 cell,letrozole suppressed PR expression,but PGRMC1 knockdown increased PR and STS expression.Our presented results highlight the important role of Pgrmc1 in modulating estrogen production when ovary-derived estrogen is limited,thereby suggesting a potential therapeutic approach for letrozole resistance.展开更多
基金This work was supported in part by the National Institutes of Health grants DK083952 and HD073070(to W.X.).
文摘Background and Aim:Sulfotransferase(SULT)-mediated sulfation and steroid sulfatase(STS)-mediated desulfation represent two critical mechanisms that regulate the chemical and functional homeostasis of endogenous and exogenous molecules.STS catalyzes the hydrolysis of steroid sulfates to form hydroxysteroids.Oxygenated cholesterol derivative oxysterols are known to be endogenous ligands of the liver X receptor(LXR),a nuclear receptor with anti-cholestasis activity,whereas the sulfated oxysterols antagonize LXR signaling.The conversion of sulfated oxysterols to their non-sulfated counterparts is catalyzed by STS.The aim of this study is to determine whether STS can alleviate cholestasis by increasing the activity of LXR.Methods:Liver-specific STS transgenic mice were created and subject to the lithocholic acid(LCA)-induced model of cholestasis.Results:Transgenic overexpression of STS in the liver promoted bile acid elimination and alleviated LCAinduced cholestasis.The protective effect of the STS transgene was associated with the activation of LXR and induction of LXR target genes,likely because of the increased conversion of the antagonistic oxysterol sulfates to the agonistic oxysterols.Conclusions:STS has a novel function in controlling the homeostasis of bile acids by regulating endogenous LXR ligands.
基金This work was supported by a research fund of Chungnam National University(No.2020-0733-01)This work was supported by Research Scholarship of Chungnam National University.
文摘In post-menopausal women,intra-mammary estrogen,which is converted from extra-ovarian estrone(E1),promotes the growth of breast cancer.Since the aromatase inhibitor letrozole does not suppress 17β-estradiol(E2)production from E1,high intra-mammary E1 concentrations impair letrozole's therapeutic efficacy.Progesterone receptor membrane component 1(Pgrmc1)is a non-classical progesterone receptor associated with breast cancer progression.In the present study,we introduced a Pgrmc1 heterozygous knockout(hetero KO)murine model exhibiting low Pgrmc1 expression,and observed estrogen levels and steroidogenic gene expression.Naïve Pgrmc1 hetero KO mice exhibited low estrogen(E2 and E1)levels and low progesterone receptor(PR)expression,compared to wild-type mice.In contrast,Pgrmc1 hetero KO mice that have been ovariectomized(OVX),including letrozole-treated OVX mice(OVX-letrozole),exhibited high estrogen levels and PR expression.Increased extra-ovarian estrogen production in Pgrmc1 hetero KO mice was observed with the induction of steroid sulfatase(STS).In MCF-7 cell,letrozole suppressed PR expression,but PGRMC1 knockdown increased PR and STS expression.Our presented results highlight the important role of Pgrmc1 in modulating estrogen production when ovary-derived estrogen is limited,thereby suggesting a potential therapeutic approach for letrozole resistance.
