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

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。

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.