研究揭示豬膽酸改善葡萄糖穩態的機制

研究揭示豬膽酸改善葡萄糖穩態的機制

作者：

小柯機器人

發布時間：2020/12/19 16:18:16

上海交通大學Wei Jia等研究人員合作發現，豬膽酸通過不同的TGR5和FXR信號機制來改善葡萄糖穩態。該研究於2020年12月17日在線發表於國際一流學術期刊《細胞—代謝》。

據研究人員介紹，豬膽酸（HCA）及其衍生物在人體血液中只存在痕量，但在豬中約佔膽汁酸（BA）庫的76％，而該物種以其對2型糖尿病的特殊耐受性而聞名。

研究人員表明，豬的BA耗竭抑制了胰高血糖素樣肽1（GLP-1）的分泌並增加了血糖水平。與牛磺熊去氧膽酸相比，在糖尿病小鼠模型中施用HCA可以更大程度地提升GLP-1分泌和葡萄糖穩態。HCA通過同時激活G蛋白偶聯BA受體TGR5和抑制類法尼醇X受體（FXR）來上調腸內分泌細胞中GLP-1的產生和分泌，這是其他BA物種中未發現的獨特機制。

 

研究人員在TGR5基因敲除、腸道FXR激活和GLP-1受體抑制等小鼠模型中驗證了這些發現。最後，研究人員在臨床隊列研究中證實，HCA種類的血清濃度降低與糖尿病有關，並且與血糖指標密切相關。

 

附：英文原文

Title: Hyocholic acid species improve glucose homeostasis through a distinct TGR5 and FXR signaling mechanism

Author: Xiaojiao Zheng, Tianlu Chen, Runqiu Jiang, Aihua Zhao, Qing Wu, Junliang Kuang, Dongnan Sun, Zhenxing Ren, Mengci Li, Mingliang Zhao, Shouli Wang, Yuqian Bao, Huating Li, Cheng Hu, Bing Dong, Defa Li, Jiayu Wu, Jialin Xia, Xuemei Wang, Ke Lan, Cynthia Rajani, Guoxiang Xie, Aiping Lu, Weiping Jia, Changtao Jiang, Wei Jia

Issue&Volume: 2020-12-17

Abstract: Hyocholic acid (HCA) and its derivatives are found in trace amounts in human bloodbut constitute approximately 76% of the bile acid (BA) pool in pigs, a species knownfor its exceptional resistance to type 2 diabetes. Here, we show that BA depletionin pigs suppressed secretion of glucagon-like peptide-1 (GLP-1) and increased bloodglucose levels. HCA administration in diabetic mouse models improved serum fastingGLP-1 secretion and glucose homeostasis to a greater extent than tauroursodeoxycholicacid. HCA upregulated GLP-1 production and secretion in enteroendocrine cells viasimultaneously activating G-protein-coupled BA receptor, TGR5, and inhibiting farnesoidX receptor (FXR), a unique mechanism that is not found in other BA species. We verifiedthe findings in TGR5 knockout, intestinal FXR activation, and GLP-1 receptor inhibitionmouse models. Finally, we confirmed in a clinical cohort, that lower serum concentrationsof HCA species were associated with diabetes and closely related to glycemic markers.

DOI: 10.1016/j.cmet.2020.11.017

Source: https://www.cell.com/cell-metabolism/fulltext/S1550-4131(20)30652-5