Chemoproteomic Profiling of Bile Acid Interacting Proteins

Zhuang, S.; Li, Q.; Cai, L.; Wang, C.*; Lei, X.*
ACS Cent. Sci. 2017, 3, 501-509

ABSTRACT: 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 […]

ABSTRACT: 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.

http://pubs.acs.org/doi/pdf/10.1021/acscentsci.7b00134