Aloe emodin promotes mucosal healing by modifying the differentiation fate of enteroendocrine cells via regulating cellular free fatty acid sensitivity  

作　　者：Weilian Bao Jiaren Lyu Guize Feng Linfeng Guo Dian Zhao Keyuan You Yang Liu Haidong Li Peng Du Daofeng Chen Xiaoyan Shen 

机构地区：[1]Department of Pharmacology&the Key Laboratory of Smart Drug Delivery Ministry of Education,School of Pharmacy,Fudan University,Shanghai 201210,China [2]Department of Natural Medicine,School of Pharmacy,Fudan University,Shanghai 201210,China [3]Department of Colorectal and Anal Surgery,Xinhua Hospital,Shanghai Jiao Tong University School of Medicine,Shanghai 200092,China [4]Shanghai Colorectal Cancer Research Center,Shanghai 200092,China

出　　处：《Acta Pharmaceutica Sinica B》2024年第9期3964-3982,共19页药学学报（英文版）

基　　金：National Natural Science Foundation of China(Nos.82030113,82130108,and 82204717);China Postdoctoral Science Foundation(Nos.BX20220069 and 2021M700864).

摘　　要：The proper differentiation and reorganization of the intestinal epithelial cell population is critical to mucosal regeneration post injury.Label retaining cells(LRCs)expressing SRY-box transcription factor 9(SOX9)promote epithelial repair by replenishing LGR5 t intestinal stem cells(ISCs).While,LRCs are also considered precursor cells for enteroendocrine cells(EECs)which exacerbate mucosal damage in inflammatory bowel disease(IBD).The factors that determine LRC-EEC differentiation and the effect of intervening in LRC-EEC differentiation on IBD remain unclear.In this study,we investigated the effects of a natural anthraquinone called aloe emodin(derived from the Chinese herb rhubarb)on mucosal healing in IBD models.Our findings demonstrated that aloe emodin effectively interfered with the differentiation to EECs and preserved a higher number of SOX9t LRCs,thereby promoting mucosal healing.Furthermore,we discovered that aloe emodin acted as an antagonist of free fatty acid receptors(FFAR1),suppressing the FFAR1-mediated Gbg/serine/threonine-protein kinase(AKT)pathway and promoting the translocation of forkhead box protein O1(FOXO1)into the nucleus,ultimately resulting in the intervention of differentiation fate.These findings reveal the effect of free fatty acid accessibility on EEC differentiation and introduce a strategy for promoting mucosal healing in IBD by regulating the FFAR1/AKT/FOXO1 signaling pathway.

关 键 词：LRCS ISCS EECs IBD SOX9 Aloe emodin FFAR1 FOXO1 

分 类 号：R735[医药卫生—肿瘤]