Bariatric surgery reveals a gut-restricted TGR5 agonist with anti-diabetic effects.
Bariatric surgery reveals a gut-restricted TGR5 agonist with anti-diabetic effects.
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减肥手术发现了一种肠道限制性TGR5激动剂，具有抗糖尿病效果。
DOI：
10.1038/s41589-020-0604-z
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发表时间：
2021-01
影响因子：
14.8
通讯作者：
Devlin AS
中科院分区：
文献类型：
--
作者：
Chaudhari SN;Harris DA;Aliakbarian H;Luo JN;Henke MT;Subramaniam R;Vernon AH;Tavakkoli A;Sheu EG;Devlin AS
减肥手术是肥胖和2型糖尿病最有效的治疗方法，与肠促胰岛素激素GLP-1水平升高和循环胆汁酸水平变化相关。然而，手术后胃肠道中单个胆汁酸的水平在很大程度上尚未研究。使用基于UPLC-MS的定量，我们观察到袖状胃切除术后小鼠和人的胃肠道中内源性胆汁酸胆酸-7-硫酸盐（CA 7S）增加。我们发现，CA 7S是一种TGR 5激动剂，可增加TGR 5表达并诱导GLP-1分泌。此外，CA 7S给药以TGR 5依赖性方式增加胰岛素抵抗小鼠的葡萄糖耐量。CA 7S仍然是肠道限制性的，最大限度地减少了先前在吸收到循环中的TGR 5激动剂中观察到的脱靶效应。通过研究手术后个体代谢物的变化，这项研究揭示了一种天然存在的TGR 5激动剂，它在保持局限于肠道的同时发挥全身性葡萄糖调节作用。
Bariatric surgery, the most effective treatment for obesity and type 2 diabetes, is associated with increased levels of the incretin hormone GLP-1 and changes in levels of circulating bile acids. The levels of individual bile acids in the GI tract following surgery, however, have remained largely unstudied. Using UPLC-MS-based quantification, we observed an increase in an endogenous bile acid, cholic acid-7-sulfate (CA7S), in the GI tract of both mice and humans after sleeve gastrectomy. We show that CA7S is a TGR5 agonist that increases Tgr5 expression and induces GLP-1 secretion. Further, CA7S administration increases glucose tolerance in insulin-resistant mice in a TGR5-dependent manner. CA7S remains gut-restricted, minimizing off-target effects previously observed for TGR5 agonists absorbed into circulation. By studying changes in individual metabolites following surgery, this study has revealed a naturally occurring TGR5 agonist that exerts systemic glucoregulatory effects while remaining confined to the gut.
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影响因子：
8.1
作者：
Kuhre RE;Wewer Albrechtsen NJ;Larsen O;Jepsen SL;Balk-Møller E;Andersen DB;Deacon CF;Schoonjans K;Reimann F;Gribble FM;Albrechtsen R;Hartmann B;Rosenkilde MM;Holst JJ
通讯作者：
Holst JJ
影响因子：
16.2
作者：
Batterham, Rachel L.;Cummings, David E.
通讯作者：
Cummings, David E.
影响因子：
3.5
作者：
Kuhre RE;Wewer Albrechtsen NJ;Deacon CF;Balk-Møller E;Rehfeld JF;Reimann F;Gribble FM;Holst JJ
通讯作者：
Holst JJ
DOI：
10.1152/ajpgi.00027.2007
发表时间：
2007-07-01
影响因子：
4.5
作者：
Hamilton, James P.;Xie, Guofeng;Hofmann, Alan F.
通讯作者：
Hofmann, Alan F.
胆汁酸主要通过进入基底外侧G蛋白偶联的胆汁酸受体触发GLP-1。
影响因子：
4.8
作者：
Brighton CA;Rievaj J;Kuhre RE;Glass LL;Schoonjans K;Holst JJ;Gribble FM;Reimann F
通讯作者：
Reimann F