Chemoproteomic Profiling of Bile Acid Interacting Proteins.
Chemoproteomic Profiling of Bile Acid Interacting Proteins.
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胆汁酸相互作用蛋白的化学蛋白质组学分析
DOI：
10.1021/acscentsci.7b00134
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发表时间：
2017-05-24
影响因子：
18.2
通讯作者：
Lei X
中科院分区：
文献类型：
--
作者：
Zhuang S;Li Q;Cai L;Wang C;Lei X
胆汁酸(BAS)是一类由肝脏中的胆固醇合成，经肠道微生物区系修饰的内源性代谢物。作为两亲性分子，bas的主要功能是帮助饮食中的脂肪消化。此外，它们还作为信号分子调节宿主体内的脂肪和葡萄糖代谢以及肠道微生物区系组成。值得注意的是，最近发现的bas的专属受体如FXR和TGR5揭示了bas信号激素的一些新的作用，这些激素在生理和病理条件下都发挥着重要的作用。BAS代谢紊乱与代谢综合征、肠道和神经退行性疾病密切相关。尽管基于BA的治疗已经在临床上实施了几十年，但BA的调节机制仍然知之甚少，蛋白质组中BA相互作用的蛋白质的全面特征仍然是未知的。在此，我们描述了一种化学蛋白质组策略，该策略使用许多结构多样化、可点击和光反应的BA探针，并结合定量质谱学来全局描述哺乳动物细胞中BA相互作用的蛋白质。已鉴定了600多个BA相互作用的蛋白质靶点，包括已知的BA内源受体和转运体。对这些新的BA相互作用蛋白的分析表明，它们主要富含在内质网(ER)应激反应和脂质代谢等功能途径中，并被预测与阿尔茨海默病、非酒精性脂肪性肝病和腹泻有很强的相关性。我们的发现将极大地提高目前对bas在人类生理和疾病中的调节作用的理解。通过化学蛋白质组学的方法，使用可点击和光反应的胆汁酸(BA)化学探针并结合定量质谱学，已经鉴定了600多个与胆汁酸(BA)相互作用的蛋白质，其中包括一些新的靶点。
Bile acids (BAs) are a family of endogenous metabolites synthesized from cholesterol in liver and modified by microbiota in gut. Being amphipathic molecules, the major function of BAs is to help with dietary lipid digestion. In addition, they also act as signaling molecules to regulate lipid and glucose metabolism as well as gut microbiota composition in the host. Remarkably, recent discoveries of the dedicated receptors for BAs such as FXR and TGR5 have uncovered a number of novel actions of BAs as signaling hormones which play significant roles in both physiological and pathological conditions. Disorders in BAs’ metabolism are closely related to metabolic syndrome and intestinal and neurodegenerative diseases. Though BA-based therapies have been clinically implemented for decades, the regulatory mechanism of BA is still poorly understood and a comprehensive characterization of BA-interacting proteins in proteome remains elusive. We herein describe a chemoproteomic strategy that uses a number of structurally diverse, clickable, and photoreactive BA-based probes in combination with quantitative mass spectrometry to globally profile BA-interacting proteins in mammalian cells. Over 600 BA-interacting protein targets were identified, including known endogenous receptors and transporters of BA. Analysis of these novel BA-interacting proteins revealed that they are mainly enriched in functional pathways such as endoplasmic reticulum (ER) stress response and lipid metabolism, and are predicted with strong implications with Alzheimer’s disease, non-alcoholic fatty liver disease, and diarrhea. Our findings will significantly improve the current understanding of BAs’ regulatory roles in human physiology and diseases. Over 600 bile acid (BA)-interacting proteins including a number of novel targets have been identified through a chemoproteomic approach using clickable and photoreactive BA-based chemical probes in combination with quantitative mass spectrometry.