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研究揭示猪胆酸改善葡萄糖稳态的机制
作者:小柯机器人 发布时间:2020/12/19 16:18:16

上海交通大学Wei Jia等研究人员合作发现,猪胆酸通过不同的TGR5和FXR信号机制来改善葡萄糖稳态。该研究于2020年12月17日在线发表于国际一流学术期刊《细胞—代谢》。

据研究人员介绍,猪胆酸(HCA)及其衍生物在人体血液中只存在痕量,但在猪中约占胆汁酸(BA)库的76%,而该物种以其对2型糖尿病的特殊耐受性而闻名。

研究人员表明,猪的BA耗竭抑制了胰高血糖素样肽1(GLP-1)的分泌并增加了血糖水平。与牛磺熊去氧胆酸相比,在糖尿病小鼠模型中施用HCA可以更大程度地提升GLP-1分泌和葡萄糖稳态。HCA通过同时激活G蛋白偶联BA受体TGR5和抑制类法尼醇X受体(FXR)来上调肠内分泌细胞中GLP-1的产生和分泌,这是其他BA物种中未发现的独特机制。
 
研究人员在TGR5基因敲除、肠道FXR激活和GLP-1受体抑制等小鼠模型中验证了这些发现。最后,研究人员在临床队列研究中证实,HCA种类的血清浓度降低与糖尿病有关,并且与血糖指标密切相关。
 
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

期刊信息

Cell Metabolism:《细胞—代谢》,创刊于2005年。隶属于细胞出版社,最新IF:22.415
官方网址:https://www.cell.com/cell-metabolism/home
投稿链接:https://www.editorialmanager.com/cell-metabolism/default.aspx