4-Phenylbutyric Acid Reduces Endoplasmic Reticulum Stress, Trypsin Activation, and Acinar Cell Apoptosis While Increasing Secretion in Rat Pancreatic Acini
4-Phenylbutyric Acid Reduces Endoplasmic Reticulum Stress, Trypsin Activation, and Acinar Cell Apoptosis While Increasing Secretion in Rat Pancreatic Acini
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DOI：
10.1097/mpa.0b013e318259f6ca
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发表时间：
2013-01-01
期刊：
影响因子：
2.9
通讯作者：
Kubisch, Constanze H.
中科院分区：
文献类型：
--
作者：
Malo, Antje;Krueger, Burkhard;Kubisch, Constanze H.
目的：内质网（ER）应激导致内质网内蛋白质错误折叠并启动未折叠蛋白反应（UPR）。未折叠蛋白反应组分参与胰腺功能并在胰腺炎期间被激活。然而，内质网应激在外分泌胰腺中的确切作用尚不清楚。本研究考察了ER伴侣4-苯基丁酸（4-PBA）对acini和UPR成分的影响。方法：用胆囊收缩素（10 pmol/L ~ 10 nmol/L）刺激大鼠腺泡，4-PBA预孵育或不预孵育。分析UPR组分，包括伴侣结合蛋白、蛋白激酶样ER激酶、x- box结合蛋白1、c-Jun nh2末端激酶、CCAAT/增强子结合蛋白同源蛋白、caspase 3和凋亡。测定4-PBA对分泌、钙和胰蛋白酶活化的影响。结果：4-苯基丁酸导致分泌增加，而胰蛋白酶与生理上胆囊收缩素的激活明显降低。4-苯丁酸抑制伴侣蛋白结合蛋白上调，抑制蛋白激酶样ER激酶和c-Jun nh2末端激酶磷酸化，抑制x- box结合蛋白1剪接和CCAAT/增强子结合蛋白同源蛋白表达，抑制caspase 3激活，抑制超生理胆囊收缩素引起的细胞凋亡。结论：4-PBA对尿素循环缺乏有促进酶分泌的作用，可抑制胰蛋白酶激活、UPR激活及促凋亡通路。这些数据为化学伴侣在胰腺疾病中的应用提供了新的视角。
Objectives: Endoplasmic reticulum (ER) stress leads to misfolded proteins inside the ER and initiates unfolded protein response (UPR). Unfolded protein response components are involved in pancreatic function and activated during pancreatitis. However, the exact role of ER stress in the exocrine pancreas is unclear. The present study examined the effects of 4-phenylbutyric acid (4-PBA), an ER chaperone, on acini and UPR components.Methods: Rat acini were stimulated with cholecystokinin (10 pmol/L to 10 nmol/L) with or without preincubation of 4-PBA. The UPR components were analyzed, including chaperone-binding protein, protein kinaselike ER kinase, X-box-binding protein 1, c-Jun NH2-terminal kinase, CCAAT/enhancer-binding protein homologous protein, caspase 3, and apoptosis. Effects of 4-PBA were measured on secretion, calcium, and trypsin activation.Results: 4-Phenylbutyric acid led to an increase of secretion, whereas trypsin activation with supraphysiological cholecystokinin was significantly reduced. 4-Phenylbutyric acid prevented chaperone-binding protein up-regulation, diminished protein kinaselike ER kinase, and c-Jun NH2-terminal kinase phosphorylation, prohibited X-box-binding protein 1 splicing and CCAAT/enhancer-binding protein homologous protein expression, caspase 3 activation, and apoptosis caused by supraphysiological cholecystokinin.Conclusion: By incubation with 4-PBA, beneficial in urea cycle deficiency, it was possible to enhance enzyme secretion to suppress trypsin activation, UPR activation, and proapoptotic pathways. The data hint new perspectives for the use of chemical chaperones in pancreatic diseases.