Bile Acids Trigger GLP-1 Release Predominantly by Accessing Basolaterally Located G Protein-Coupled Bile Acid Receptors.
Bile Acids Trigger GLP-1 Release Predominantly by Accessing Basolaterally Located G Protein-Coupled Bile Acid Receptors.
复制标题
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。
DOI：
10.1210/en.2015-1321
复制
发表时间：
2015-11
期刊：
影响因子：
4.8
通讯作者：
Reimann F
中科院分区：
文献类型：
--
作者：
Brighton CA;Rievaj J;Kuhre RE;Glass LL;Schoonjans K;Holst JJ;Gribble FM;Reimann F
胆汁酸是公认的刺激胰高血糖素样肽-1 （GLP-1）分泌。这种作用归因于G蛋白偶联胆汁酸受体GPBAR1 （TGR5）的激活，尽管其他潜在的胆汁酸传感器包括核法内酯受体和根尖钠偶联胆汁酸转运体ASBT。本研究的目的是确定GLP-1释放的重要途径，并确定胆汁酸是否从根尖或基底外侧室靶向其受体对分泌GLP-1的l细胞。利用在l细胞中特异性表达荧光传感器的转基因小鼠，我们观察到牛磺酸去氧胆酸盐（TDCA）和牛磺酸胆酸盐（TLCA）增加了细胞内cAMP和Ca2+。在原代肠道培养中，TDCA是比牛磺酸胆酸（TCA）和TLCA更有效的GLP-1促分泌剂，与TDCA更强的Ca2+反应相关。利用优化的小体积Ussing实验室测量GLP-1分泌，我们发现GPBAR1激动剂和TDCA从基底外侧比从管腔方向更好地刺激GLP-1释放，并且当肠道组织用ASBT抑制剂预处理时，管腔TDCA无效。ASBT抑制在非极化原代培养中无显著效果。对灌注大鼠肠道的研究证实，血管给予的TDCA比管腔给予的TDCA更有效。在TLCA和TDCA作用下，gpbar1敲除小鼠的肠道原代培养和室装组织均未分泌GLP-1。我们得出结论，胆汁酸对GLP-1分泌的作用主要是由位于基底外侧l细胞膜上的GPBAR1介导的，这表明刺激肠道激素分泌可能包括吸收后机制。
Bile acids are well-recognized stimuli of glucagon-like peptide-1 (GLP-1) secretion. This action has been attributed to activation of the G protein–coupled bile acid receptor GPBAR1 (TGR5), although other potential bile acid sensors include the nuclear farnesoid receptor and the apical sodium-coupled bile acid transporter ASBT. The aim of this study was to identify pathways important for GLP-1 release and to determine whether bile acids target their receptors on GLP-1–secreting L-cells from the apical or basolateral compartment. Using transgenic mice expressing fluorescent sensors specifically in L-cells, we observed that taurodeoxycholate (TDCA) and taurolithocholate (TLCA) increased intracellular cAMP and Ca2+. In primary intestinal cultures, TDCA was a more potent GLP-1 secretagogue than taurocholate (TCA) and TLCA, correlating with a stronger Ca2+ response to TDCA. Using small-volume Ussing chambers optimized for measuring GLP-1 secretion, we found that both a GPBAR1 agonist and TDCA stimulated GLP-1 release better when applied from the basolateral than from the luminal direction and that luminal TDCA was ineffective when intestinal tissue was pretreated with an ASBT inhibitor. ASBT inhibition had no significant effect in nonpolarized primary cultures. Studies in the perfused rat gut confirmed that vascularly administered TDCA was more effective than luminal TDCA. Intestinal primary cultures and Ussing chamber–mounted tissues from GPBAR1-knockout mice did not secrete GLP-1 in response to either TLCA or TDCA. We conclude that the action of bile acids on GLP-1 secretion is predominantly mediated by GPBAR1 located on the basolateral L-cell membrane, suggesting that stimulation of gut hormone secretion may include postabsorptive mechanisms.