Hepatic steroid sulfatase critically determines estrogenic activities of conjugated equine estrogens in human cells in vitro and in mice
JournalJournal of Biological Chemistry
PublisherAmerican Society for Biochemistry and Molecular Biology Inc.
MetadataShow full item record
AbstractConjugated equine estrogens (CEEs), whose brand name is Premarin, are widely used as a hormone-replacement therapy (HRT) drug to manage postmenopausal symptoms in women. Extracted from pregnant mare urine, CEEs are composed of nearly a dozen estrogens existing in an inactive sulfated form. To determine whether the hepatic steroid sulfatase (STS) is a key contributor to the efficacy of CEEs in HRT, we performed estrogen-responsive element (ERE) reporter gene assay, real-time PCR, and UPLC-MS/MS to assess the STS-dependent and inflammation-responsive estrogenic activity of CEEs in HepG2 cells and human primary hepatocytes. Using liver-specific STS-expressing transgenic mice, we also evaluated the effect of STS on the estrogenic activity of CEEs in vivo. We observed that CEEs induce activity of the ERE reporter gene in an STS-dependent manner and that genetic or pharmacological inhibition of STS attenuates CEE estrogenic activity. In hepatocytes, inflammation enhanced CEE estrogenic activity by inducing STS gene expression. The inflammation-responsive estrogenic activity of CEEs, in turn, attenuated inflammation through the anti-inflammatory activity of the active estrogens. In vivo, transgenic mice with liver-specific STS expression exhibited markedly increased sensitivity to CEE-induced estrogenic activity in the uterus resulting from increased levels of liver-derived and circulating estrogens. Our results reveal a critical role of hepatic STS in mediating the hormone-replacing activity of CEEs. We propose that caution needs to be applied when Premarin is used in patients with chronic inflammatory liver diseases because such patients May have heightened sensitivity to CEEs due to the inflammatory induction of STS activity. Copyright 2019 Feng et al.
SponsorsThis work was supported in part by National Institutes of Health Grants DK083952, ES023438 (to W. X.), and GM121550 (to H. W.). The authors declare that they have no conflicts of interest with the contents of this article.
Identifier to cite or link to this itemhttps://www.scopus.com/inward/record.uri?eid=2-s2.0-85070738514&doi=10.1074%2fjbc.RA119.009181&partnerID=40&md5=53fc6d64c284cef9f6838b6195bc9232; http://hdl.handle.net/10713/10413
- Inflammatory regulation of steroid sulfatase: A novel mechanism to control estrogen homeostasis and inflammation in chronic liver disease.
- Authors: Jiang M, Klein M, Zanger UM, Mohammad MK, Cave MC, Gaikwad NW, Dias NJ, Selcer KW, Guo Y, He J, Zhang X, Shen Q, Qin W, Li J, Li S, Xie W
- Issue date: 2016 Jan
- Steroid sulfatase mediated growth Sof human MG-63 pre-osteoblastic cells.
- Authors: Dias NJ, Selcer KW
- Issue date: 2014 Oct
- Hepatic overexpression of steroid sulfatase ameliorates mouse models of obesity and type 2 diabetes through sex-specific mechanisms.
- Authors: Jiang M, He J, Kucera H, Gaikwad NW, Zhang B, Xu M, O'Doherty RM, Selcer KW, Xie W
- Issue date: 2014 Mar 21
- Molecular characterization of a B-ring unsaturated estrogen: implications for conjugated equine estrogen components of premarin.
- Authors: Hsieh RW, Rajan SS, Sharma SK, Greene GL
- Issue date: 2008 Jan
- Sex-Dimorphic and Sex Hormone-Dependent Role of Steroid Sulfatase in Adipose Inflammation and Energy Homeostasis.
- Authors: Bi Y, Jiang M, Guo W, Guan X, Xu M, Ren S, Yang D, Gaikwad NW, Selcer KW, Xie W
- Issue date: 2018 Sep 1