Roux-en-Y gastric bypass enhances insulin secretion in type 2 diabetes via FXR-mediated TRPA1 expression
Roux-en-Y gastric bypass enhances insulin secretion in type 2 diabetes via FXR-mediated TRPA1 expression
复制标题
Roux-en-Y胃绕道手术通过FXR介导的TRPA1表达增强2型糖尿病的胰岛素分泌
DOI：
10.1016/j.molmet.2019.08.009
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发表时间：
2019-11-01
影响因子：
8.1
通讯作者：
Ma, Xiaosong
中科院分区：
文献类型：
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作者：
Kong, Xiangchen;Tu, Yifan;Ma, Xiaosong
目的：Roux-en-Y胃旁路手术（RYGB）改善2型糖尿病患者一期葡萄糖刺激胰岛素分泌（GSIS）。目前尚不清楚它是如何做到的。Farnesoid X受体（FXR）是胆汁酸（BAs）的核受体，与减肥手术有关。此外，瞬时受体电位锚蛋白1 （TRPA1）通道在胰腺β细胞中表达并参与胰岛素分泌。我们旨在探讨BAs/FXR和TRPA1在RYGB后糖尿病大鼠GSIS改善中的作用。方法：对自发性糖尿病Goto-Kakizaki （GK）大鼠、FXR或TRPA1转基因小鼠进行RYGB或假手术。采用qPCR和western blotting检测胰岛基因和蛋白的表达。采用膜片钳技术研究了单个β细胞的电生理特性。FXR和组蛋白乙酰转移酶类固醇受体共激活因子-1 （SRC1）与TRPA1启动子的结合，以及TRPA1启动子上乙酰化组蛋白H3 （ACH3）的水平通过ChIP测定。采用酶联免疫吸附试验或静脉糖耐量试验（IVGTT）测定GSIS。结果：RYGB可提高GK大鼠和完整胰岛大鼠体内GSIS，尤其是GSIS一期，并可改善GK大鼠的高血糖。重要的是，RYGB在TRPA1缺陷小鼠中的作用减弱。此外，GK β细胞显示TRPA1表达和电流显著降低。膜片钳记录显示TRPA1(-/-) β细胞表现出明显的超极化和葡萄糖诱发动作电位放电减少，这与GSIS受损有关。RYGB恢复GK β细胞中TRPA1的表达和电流。这伴随着葡萄糖诱发的电活动和胰岛素分泌的改善。此外，rygb诱导的TRPA1表达涉及BAs/ fxr介导的SRC1募集，在TRPA1启动子处促进ACH3。结论：BAs/FXR/SRC1轴介导的TRPA1表达恢复在RYGB后GK大鼠GSIS增强和糖尿病缓解中起关键作用。(C) 2019作者。Elsevier GmbH出版。
Objective: Roux-en-Y gastric bypass surgery (RYGB) improves the first phase of glucose-stimulated insulin secretion (GSIS) in patients with type 2 diabetes. How it does so remains unclear. Farnesoid X receptor (FXR), the nuclear receptor of bile acids (BAs), is implicated in bariatric surgery. Moreover, the transient receptor potential ankyrin 1 (TRPA1) channel is expressed in pancreatic beta-cells and involved in insulin secretion. We aimed to explore the role of BAs/FXR and TRPA1 in improved GSIS in diabetic rats after RYGB.Methods: RYGB or sham surgery was conducted in spontaneous diabetic Goto-Kakizaki (GK) rats, or FXR or TRPA1 transgenic mice. Gene and protein expression of islets were assessed by qPCR and western blotting. Electrophysiological properties of single beta-cells were studied using patch-clamp technique. Binding of FXR and histone acetyltransferase steroid receptor coactivator-1 (SRC1) to the TRPA1 promoter, acetylated histone H3 (ACH3) levels at the TRPA1 promoter were determined using ChIP assays. GSIS was measured using enzyme-linked immunosorbent assays or intravenous glucose tolerance test (IVGTT).Results: RYGB increases GSIS, particularly the first-phase of GSIS in both intact islets and GK rats in vivo, and ameliorates hyperglycemia of GK rats. Importantly, the effects of RYGB were attenuated in TRPA1 -deficient mice. Moreover, GK beta-cells displayed significantly decreased TRPA1 expression and current. Patch-clamp recording revealed that TRPA1(-/- )beta-cells displayed a marked hyperpolarization and decreased glucose-evoked action potential firing, which was associated with impaired GSIS. RYGB restored TRPA1 expression and current in GK beta-cells. This was accompanied by improved glucose-evoked electrical activity and insulin secretion. Additionally, RYGB-induced TRPA1 expression involved BAs/FXR-mediated recruitment of SRC1, promoting ACH3 at the promoter of TRPA1.Conclusions: The BAs/FXR/SRC1 axis-mediated restoration of TRPA1 expression plays a critical role in the enhanced GSIS and remission of diabetes in GK rats after RYGB. (C) 2019 The Authors. Published by Elsevier GmbH.