The G Protein-Coupled Bile Acid Receptor, TGR5, Stimulates Gallbladder Filling
The G Protein-Coupled Bile Acid Receptor, TGR5, Stimulates Gallbladder Filling
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DOI：
10.1210/me.2010-0460
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发表时间：
2011-06-01
影响因子：
--
通讯作者：
Mangelsdorf, David J.
中科院分区：
文献类型：
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作者：
Li, Tingting;Holmstrom, Sam R.;Mangelsdorf, David J.
TGR 5是存在于棕色脂肪组织和肠中的G蛋白偶联胆汁酸受体，其激动作用增加能量消耗并降低血糖。因此，它是治疗人类代谢疾病的有吸引力的药物靶标。然而，TGR 5也在胆囊中高度表达，其功能不太清楚。在这里，我们证明TGR 5刺激胆汁填充胆囊。通过给予天然TGR 5激动剂石胆酸或合成TGR 5激动剂INT-777，野生型小鼠的胆囊体积增加，但Tgr 5（-/-）小鼠未增加。这些作用与成纤维细胞生长因子15无关，成纤维细胞生长因子15是一种肠道激素，以前被证明可以刺激胆囊充盈。使用胆囊组织的离体分析表明，TGR 5激活增加cAMP浓度，并以TGR 5依赖性方式引起平滑肌松弛。这些数据揭示了一种新的，胆囊的内在机制，调节胆囊收缩。他们进一步建议，应评估TGR 5激动剂对人胆囊的影响，因为它们被开发用于治疗代谢疾病。（分子内分泌学25：1066-1071，2011）
TGR5 is a G protein-coupled bile acid receptor present in brown adipose tissue and intestine, where its agonism increases energy expenditure and lowers blood glucose. Thus, it is an attractive drug target for treating human metabolic disease. However, TGR5 is also highly expressed in gallbladder, where its functions are less well characterized. Here, we demonstrate that TGR5 stimulates the filling of the gallbladder with bile. Gallbladder volume was increased in wild-type but not Tgr5(-/-) mice by administration of either the naturally occurring TGR5 agonist, lithocholic acid, or the synthetic TGR5 agonist, INT-777. These effects were independent of fibroblast growth factor 15, an enteric hormone previously shown to stimulate gallbladder filling. Ex vivo analyses using gallbladder tissue showed that TGR5 activation increased cAMP concentrations and caused smooth muscle relaxation in a TGR5-dependent manner. These data reveal a novel, gallbladder-intrinsic mechanism for regulating gallbladder contractility. They further suggest that TGR5 agonists should be assessed for effects on human gallbladder as they are developed for treating metabolic disease. ( Molecular Endocrinology 25: 1066-1071, 2011)