Bile acid metabolism and signaling in health and disease:molecular mechanisms and therapeutic targets  

作　　者：Joshua S.Fleishman Sunil Kumar 

机构地区：[1]Department of Pharmaceutical Sciences,College of Pharmacy and Health Sciences,St.John’s University,Queens,NY,USA

出　　处：《Signal Transduction and Targeted Therapy》2024年第5期2014-2064,共51页信号转导与靶向治疗（英文）

基　　金：supported by a seed grant from St.John’s University College of Pharmacy&Health Sciences.

摘　　要：Bile acids,once considered mere dietary surfactants,now emerge as critical modulators of macronutrient(lipid,carbohydrate,protein)metabolism and the systemic pro-inflammatory/anti-inflammatory balance.Bile acid metabolism and signaling pathways play a crucial role in protecting against,or if aberrant,inducing cardiometabolic,inflammatory,and neoplastic conditions,strongly influencing health and disease.No curative treatment exists for any bile acid influenced disease,while the most promising and well-developed bile acid therapeutic was recently rejected by the FDA.Here,we provide a bottom-up approach on bile acids,mechanistically explaining their biochemistry,physiology,and pharmacology at canonical and non-canonical receptors.Using this mechanistic model of bile acids,we explain how abnormal bile acid physiology drives disease pathogenesis,emphasizing how ceramide synthesis may serve as a unifying pathogenic feature for cardiometabolic diseases.We provide an in-depth summary on pre-existing bile acid receptor modulators,explain their shortcomings,and propose solutions for how they may be remedied.Lastly,we rationalize novel targets for further translational drug discovery and provide future perspectives.Rather than dismissing bile acid therapeutics due to recent setbacks,we believe that there is immense clinical potential and a high likelihood for the future success of bile acid therapeutics.

关 键 词：METABOLISM rejected SHORTCOMINGS 

分 类 号：R589[医药卫生—内分泌]