Center for Translational Medicine, Shanghai Key Laboratory of Diabetes Mellitus and Shanghai Key Laboratory of Sleep Disordered Breathing, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, China.
Department of Hepatobiliary Surgery, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing 210093, China.
Cell Metab. 2021 Apr 6;33(4):791-803.e7. doi: 10.1016/j.cmet.2020.11.017. Epub 2020 Dec 17.
Hyocholic acid (HCA) and its derivatives are found in trace amounts in human blood but constitute approximately 76% of the bile acid (BA) pool in pigs, a species known for its exceptional resistance to type 2 diabetes. Here, we show that BA depletion in pigs suppressed secretion of glucagon-like peptide-1 (GLP-1) and increased blood glucose levels. HCA administration in diabetic mouse models improved serum fasting GLP-1 secretion and glucose homeostasis to a greater extent than tauroursodeoxycholic acid. HCA upregulated GLP-1 production and secretion in enteroendocrine cells via simultaneously activating G-protein-coupled BA receptor, TGR5, and inhibiting farnesoid X receptor (FXR), a unique mechanism that is not found in other BA species. We verified the findings in TGR5 knockout, intestinal FXR activation, and GLP-1 receptor inhibition mouse models. Finally, we confirmed in a clinical cohort, that lower serum concentrations of HCA species were associated with diabetes and closely related to glycemic markers.
胆酸 (HCA) 及其衍生物在人血液中以痕量存在，但在以对 2 型糖尿病具有极高抗性而闻名的猪中，占胆汁酸 (BA) 池的约 76%。在这里，我们表明，猪的 BA 耗竭会抑制胰高血糖素样肽-1 (GLP-1) 的分泌并增加血糖水平。与牛磺熊脱氧胆酸相比，在糖尿病小鼠模型中给予 HCA 可更大程度地改善血清空腹 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 和抑制法尼醇 X 受体 (FXR)，以一种在其他 BA 物种中未发现的独特机制，上调肠内分泌细胞中 GLP-1 的产生和分泌。我们在 TGR5 敲除、肠道 FXR 激活和 GLP-1 受体抑制小鼠模型中验证了这些发现。最后，我们在临床队列中证实，较低的 HCA 种类血清浓度与糖尿病相关，并与血糖标志物密切相关。
