Inflammatory regulation of steroid sulfatase: A novel mechanism to control estrogen homeostasis and inflammation in chronic liver disease

JOURNAL OF HEPATOLOGY

卷:64

Article

Jiang, Mengxi^1,2  Klein, Marcus^3,4  Zanger, Ulrich M.^3,4  Mohammad, Mohammad K.⁵  Cave, Matthew C.⁵  Gaikwad, Nilesh W.^6,7  Dias, Natasha J.⁸  Selcer, Kyle W.⁸  Guo, Yan^1,2,9  He, Jinhan¹⁰  Zhang, Xiuhui¹¹  Shen, Qiujin¹²  Qin, Wenxin¹²  Li, Jiang^1,2  Li, Song^1,2  Xie, Wen^1,2,13 

[1] Univ Pittsburgh, Ctr Pharmacogenet, Pittsburgh, PA 15261 USA

[2] Univ Pittsburgh, Dept Pharmaceut Sci, Pittsburgh, PA 15261 USA

[3] Dr Margarete Fischer Bosch Inst Clin Pharmacol, Stuttgart, Germany

[4] Univ Tubingen, Tubingen, Germany

[5] Univ Louisville, Sch Med, Dept Med, Div Gastroenterol Hepatol & Nutr, Louisville, KY 40292 USA

[6] Univ Calif Davis, Dept Nutr, Davis, CA 95616 USA

[7] Univ Calif Davis, Dept Environm Toxicol, Davis, CA 95616 USA

[8] Duquesne Univ, Dept Biol Sci, Pittsburgh, PA 15219 USA

[9] Shanghai Jiao Tong Univ, Sch Med, Dept Pathol, Ruijin Hosp, Shanghai 200030, Peoples R China

[10] Sichuan Univ, Dept Pharm, West China Hosp, Chengdu 610064, Sichuan, Peoples R China

[11] Sichuan Univ, Dept Pathol, West China Hosp, Chengdu 610064, Sichuan, Peoples R China

[12] Shanghai Jiao Tong Univ, Sch Med, State Key Lab Oncogenes & Related Genes, Shanghai Canc Inst,Renji Hosp, Shanghai 200030, Peoples R China

[13] Univ Pittsburgh, Dept Pharmacol & Chem Biol, Pittsburgh, PA USA

关键词: Steroid sulfatase;    Estrogens;    Estrogen metabolism;    Inflammation;    Liver disease;   

DOI  :  10.1016/j.jhep.2015.07.022

来源: Elsevier

【 摘 要 】

Background & Aims: Chronic inflammatory liver diseases are associated with estrogen excess and feminization in men, which is thought to be due to compromised liver function to break down estrogens. The goal of this study is to determine whether the inflammatory induction of steroid sulfatase (STS), which converts inactive estrogen sulfates to active estrogens, may have contributed to the estrogen excess in chronic liver disease. Methods: We performed bioinformatic analysis, real-time PCR, immunohistochemistry, and UPLC/MS-MS to analyze hepatic STS expression and serum estrogen levels in patients with chronic liver diseases. The crosstalk between NF-kappa B pathway and STS-regulated estrogen signaling was investigated by electrophoretic mobility shift assay, chromatin immunoprecipitation, luciferase assay and gene knockdown experiments in human hepatocytes. Results: Hepatic STS was induced in patients with chronic inflammatory liver diseases, which was accompanied by increased circulating estrogen levels. The human STS gene, but not the mouse Sts gene, was induced by inflammatory stimuli in hepatic cells. Mechanistically, STS was established as a novel NF-kappa B target gene, whose induction facilitated the conversion of inactive estrogen sulfates to active estrogens, and consequently attenuated the inflammatory response. In contrast, genetic or pharmacological inhibition of STS or a direct blockade of estrogen signaling sensitized liver cells to the transcriptional activation of NF-kappa B and inflammatory response, possibly through the inhibition of I kappa B kinase activation. Conclusions: Our results suggest a negative feedback loop in chronic inflammatory liver diseases, in which the inflammatory activation of NF-kappa B induces STS gene expression. The induced STS facilitates the conversion of inactive estrogen sulfates to active estrogens, which in return attenuates the NF-kappa B-mediated inflammation. (C) 2015 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

【 授权许可】

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