Carbonic anhydrase 8 (CAR8) negatively regulates GLP-1 secretion from enteroendocrine cells in response to long-chain fatty acids
Carbonic anhydrase 8 (CAR8) negatively regulates GLP-1 secretion from enteroendocrine cells in response to long-chain fatty acids
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碳酸酐酶8 （CAR8）负性调节肠内分泌细胞对长链脂肪酸的GLP-1分泌
DOI：
10.1152/ajpgi.00312.2020
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发表时间：
2021-04-01
影响因子：
4.5
通讯作者：
Inagaki, Nobuya
中科院分区：
文献类型：
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作者：
Fujiwara, Yuta;Yamane, Shunsuke;Inagaki, Nobuya
胰高血糖素样肽-1（GLP-1）是肠内分泌前胰高血糖素原（PPG）表达细胞（传统上称为L细胞）响应增强胰岛素分泌的管腔营养素而分泌的肠促胰岛素。除了目前使用的肠促胰岛素相关药物外，内源性GLP-1分泌的增加可能是糖尿病治疗的新治疗靶点。在这项研究中，我们发现PPG细胞基本上表达碳酸酐酶8（CAR 8），据报道，CAR 8可抑制肌醇1，4，5-三磷酸（IP 3）与IP 3受体的结合以及随后的神经元细胞内质网Ca 2+外流。使用STC-1细胞的体外实验表明，Car 8敲低增加了长链脂肪酸（LCFA）刺激的GLP-1分泌。在磷脂酶C（PLC）抑制剂存在下，这种作用降低;此外，Car 8敲低增加了α-亚麻酸引起的细胞内Ca 2+升高，表明CAR 8通过PLC/IP 3/Ca 2 thorn途径对GLP-1分泌发挥作用。与野生型同窝小鼠相比，Car 8（wdl）无效突变小鼠对经口玉米油给药的GLP-1反应显著增加，肠道GLP-1含量无显著变化。这些结果表明，CAR 8负调节GLP-1分泌从PPG细胞响应LCFA，提示可能性增强餐后GLP-1分泌CAR 8 inhibition.NEW & NOTEWORTHY这项研究集中在GLP-1分泌的碳酸酐酶8（CAR 8）从肠内分泌前胰高血糖素原（PPG）-表达细胞的生理意义。我们发现CAR 8在体外和体内LCFA诱导的GLP-1分泌中具有抑制作用，这表明通过CAR 8抑制增加餐后GLP-1分泌来治疗糖尿病和肥胖症的新方法。
Glucagon-like peptide-1 (GLP-1) is an incretin secreted from enteroendocrine preproglucagon (PPG)-expressing cells (traditionally known as L cells) in response to luminal nutrients that potentiates insulin secretion. Augmentation of endogenous GLP-1 secretion might well represent a novel therapeutic target for diabetes treatment in addition to the incretin-associated drugs currently in use. In this study, we found that PPG cells substantially express carbonic anhydrase 8 (CAR8), which has been reported to inhibit inositol 1,4,5-trisphosphate (IP3) binding to the IP3 receptor and subsequent Ca2+ efflux from the endoplasmic reticulum in neuronal cells. In vitro experiments using STC-1 cells demonstrated that Car8 knockdown increases long-chain fatty acid (LCFA)-stimulated GLP-1 secretion. This effect was reduced in the presence of phospholipase C (PLC) inhibitor; in addition, Car8 knockdown increased the intracellular Ca2+ elevation caused by a-linolenic acid, indicating that CAR8 exerts its effect on GLP-1 secretion via the PLC/IP3/Ca2 thorn pathway. Car8(wdl) null mutant mice showed significant increase in GLP-1 response to oral corn oil administration compared with that in wild-type littermates, with no significant change in intestinal GLP-1 content. These results demonstrate that CAR8 negatively regulates GLP-1 secretion from PPG cells in response to LCFAs, suggesting the possibility of augmentation of postprandial GLP-1 secretion by CAR8 inhibition.NEW & NOTEWORTHY This study focused on the physiological significance of carbonic anhydrase 8 (CAR8) in GLP-1 secretion from enteroendocrine preproglucagon (PPG)-expressing cells. We found an inhibitory role of CAR8 in LCFA-induced GLP-1 secretion in vitro and in vivo, suggesting a novel therapeutic approach to diabetes and obesity through augmentation of postprandial GLP-1 secretion by CAR8 inhibition.