硫酸胆固醇的生理功能及其在相关疾病中的作用

doi:10.3969/j.issn.1674-8115.2021.03.015

上海交通大学学报(医学版) ›› 2021, Vol. 41 ›› Issue (3): 371-375.doi: 10.3969/j.issn.1674-8115.2021.03.015

硫酸胆固醇的生理功能及其在相关疾病中的作用

蒋悦庭¹(), 倪佳英¹, 郭沈睿¹, 李菡¹, 庄雨佳¹, 王锋¹^,²()

^1.上海交通大学基础医学院免疫与微生物学系，上海 200025
^2.上海交通大学医学院上海市免疫学研究所，上海 200025

收稿日期:2020-02-17 出版日期:2021-03-28 发布日期:2021-04-06
通讯作者: 王锋 E-mail:syrinx@sjtu.edu.cn;wangfeng16@sjtu.edu.cn
作者简介:蒋悦庭（1997—），女，本科生；电子信箱：syrinx@sjtu.edu.cn。
基金资助:
国家重点研发计划(SQ2018YFA090045-01);国家自然科学基金(81771739);上海市科学技术委员会基础研究项目(18JC1414100);上海高水平地方高校创新团队(SSMU-ZDCX20180101)

Physiological function of cholesterol sulfate and its role in related diseases

Yue-ting JIANG¹(), Jia-ying NI¹, Shen-rui GUO¹, Han LI¹, Yu-jia ZHUANG¹, Feng WANG¹^,²()

^1.Department of Immunology and Microbiology, Shanghai Jiao Tong University College of Basic Medicine Sciences, Shanghai 200025, China
^2.Shanghai Jiao Tong University, Shanghai Institute of Immunology, Shanghai 200025, China

Received:2020-02-17 Online:2021-03-28 Published:2021-04-06
Contact: Feng WANG E-mail:syrinx@sjtu.edu.cn;wangfeng16@sjtu.edu.cn
Supported by:
National Key Research and Development Program of China(SQ2018YFA090045-01);National Natural Science Foundation of China(81771739);Basic Research Project of Shanghai Municipal Commission of Science and Technology(18JC1414100);Innovative Research Team of High-Level Local Universities in Shanghai(SSMU-ZDCX20180101)

摘要/Abstract

摘要：

硫酸胆固醇（cholesterol sulfate，CS）是人体中重要的类固醇硫酸酯，由胞浆磺基转移酶（sulfotransferase，SULT）2B1b催化合成，发挥多种重要的生理作用。其广泛分布于人体，如皮肤、肾上腺、肝脏、肺、脑和子宫内膜等。CS在表皮中参与角质层角化套膜的形成和角质细胞分化标志物的表达，从而调节表皮脱屑和屏障功能；在免疫系统胸腺细胞形成的过程中CS抑制T细胞受体信号的传递，并且CS/胆固醇比例直接影响T细胞的胸腺选择，由此参与成熟T细胞受体组库的塑造；CS通过减少氧化应激、维持线粒体膜稳定和增加能量储备调节脑代谢和发挥神经保护效应。此外，CS还通过调节功能蛋白的活性参与多种疾病的发生发展过程。催化CS脱硫的类固醇硫酸酯酶（steroid sulfatase，STS）基因发生缺失突变直接导致了X连锁鱼鳞病（X-linked ichthyosis，XLI）的发生；CS通过促进β淀粉样蛋白（amyloid β-protein，Aβ）聚集参与阿尔茨海默病的发生发展；CS通过抑制肝细胞核因子4α（hepatocyte nuclear factor 4α，HNF4α）的活化来调控糖异生，其衍生物有望用于治疗2型糖尿病；CS在多种癌症中均有异常表达，可与基质金属蛋白酶-7（matrix metalloproteinase-7，MMP-7）相互作用诱导癌细胞的聚集和转移。现阶段的研究重点是在病理生理条件下揭示其具体的分子机制，并由此设计可行的临床治疗方案。

关键词: 硫酸胆固醇, 角质细胞, T细胞信号, 糖代谢, 癌症

Abstract:

Cholesterol sulfate (CS), synthesized by sulfotransferase (SULT) 2B1b, is an important steroid sulfate and plays important physiological roles in the human body. It is widely distributed in human body, such as skin, adrenal gland, liver, lung, brain and endometrium. CS participates in the formation of cornified envelopes and the expression of keratinocyte differentiation markers in the epidermis, thereby regulating epidermal desquamation and barrier function. CS inhibits T cell signaling during thymocyte development in the immune system, and CS/ Cholesterol ratio directly affects thymic selection for T cells, thereby participating in the shaping of T cell receptor repertoire. CS regulates brain metabolism and exerts neuroprotective effects by reducing oxidative stress, maintaining mitochondrial membrane stability and increasing energy reserves. In addition, CS also contributes to the development of many diseases by regulating the activity of functional proteins. The deletion and mutation of steroid sulfatase (STS) gene, which catalyzes the desulfurization of CS, directly leads to the occurrence of X-linked ichthyosis. CS is involved in the development of Alzheimer's disease by promoting the aggregation of amyloid β - protein (Aβ). CS regulates gluconeogenesis by inhibiting the activation of hepatocyte nuclear factor 4α (HNF4α). Thus CS is expected to treat type 2 diabetes. CS has abnormal expression in a variety of cancers, and can interact with matrix metalloproteinase-7 (MMP-7) to induce the aggregation and metastasis of cancer cells. The main challenges and research priorities at this stage are to reveal specific molecular mechanisms under different physiological and pathological conditions and to design feasible clinical treatments.

Key words: cholesterol sulfate (CS), keratinocyte, T cell signaling, glycometabolism, cancer

中图分类号:

R392.11

蒋悦庭, 倪佳英, 郭沈睿, 李菡, 庄雨佳, 王锋. 硫酸胆固醇的生理功能及其在相关疾病中的作用[J]. 上海交通大学学报(医学版), 2021, 41(3): 371-375.

Yue-ting JIANG, Jia-ying NI, Shen-rui GUO, Han LI, Yu-jia ZHUANG, Feng WANG. Physiological function of cholesterol sulfate and its role in related diseases[J]. JOURNAL OF SHANGHAI JIAOTONG UNIVERSITY (MEDICAL SCIENCE), 2021, 41(3): 371-375.

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硫酸胆固醇的生理功能及其在相关疾病中的作用

Physiological function of cholesterol sulfate and its role in related diseases

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