Mitochondrial Dysfunction, Through Impaired Autophagy, Leads to Endoplasmic Reticulum Stress, Deregulated Lipid Metabolism, and Pancreatitis in Animal Models.
Mitochondrial Dysfunction, Through Impaired Autophagy, Leads to Endoplasmic Reticulum Stress, Deregulated Lipid Metabolism, and Pancreatitis in Animal Models.
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DOI：
10.1053/j.gastro.2017.10.012
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发表时间：
2018-03
期刊：
影响因子：
29.4
通讯作者：
Gukovskaya AS
中科院分区：
文献类型：
--
作者：
Biczo G;Vegh ET;Shalbueva N;Mareninova OA;Elperin J;Lotshaw E;Gretler S;Lugea A;Malla SR;Dawson D;Ruchala P;Whitelegge J;French SW;Wen L;Husain SZ;Gorelick FS;Hegyi P;Rakonczay Z Jr;Gukovsky I;Gukovskaya AS
对于引发和促进急性胰腺炎（AP）的信号通路知之甚少。 AP 的发病机制与胞浆 Ca2+ 异常增加、线粒体功能障碍、自噬受损和内质网 (ER) 应激有关。我们分析了这些功能障碍的机制及其相互关系，以及它们如何促进小鼠和大鼠 AP 的发展。通过给予 L-精氨酸（也在大鼠中）、雨蛙素、胆汁酸或诱导 AP 的饮食，在 C57BL/6J 小鼠（对照）和缺乏肽基脯氨酰异构酶 D（亲环蛋白 D，由 Ppid 编码）的小鼠中诱导胰腺炎。在胰腺组织、腺泡细胞和分离的线粒体中测量了胰腺炎、线粒体功能、自噬、内质网应激和脂质代谢的参数。一些患有 AP 的小鼠被给予海藻糖以增强自噬效率。通过免疫荧光分析人胰腺炎组织。 AP 小鼠胰腺中的线粒体功能障碍是由线粒体 Ca2+ 超载或通过 Ca2+ 超载无关途径引起的，该途径涉及 ATP 合酶活性降低（从给予 L-精氨酸的大鼠或小鼠中分离的胰腺线粒体中 80% 被抑制）。两条途径均由亲环蛋白 D 介导并导致线粒体去极化和断裂。线粒体功能障碍导致胰腺内质网应激、自噬受损和脂质代谢失调。这些病理反应在亲环蛋白 D 敲除小鼠中被消除。给予 L-精氨酸 AP 小鼠体内海藻糖很大程度上可以防止胰蛋白酶原激活、坏死和其他胰腺损伤参数。与正常胰腺相比，胰腺炎患者的组织具有线粒体损伤和自噬受损的标志。在不同的动物模型中，我们发现线粒体功能障碍和自噬受损作为其主要下游效应器在 AP 的发展中发挥着核心作用。特别是，涉及亲环蛋白 D 与 ATP 合酶相互作用增强的途径介导 L-精氨酸诱导的胰腺炎，这是一种严重 AP 模型，其发病机制仍不清楚。可以制定恢复线粒体和/或自噬功能的策略来治疗 AP。
Little is known about the signaling pathways that initiate and promote acute pancreatitis (AP). The pathogenesis of AP has been associated with abnormal increases in cytosolic Ca2+, mitochondrial dysfunction, impaired autophagy, and endoplasmic reticulum (ER) stress. We analyzed the mechanisms of these dysfunctions and their relationships, and how these contribute to development of AP in mice and rats. Pancreatitis was induced in C57BL/6J mice (control) and mice deficient in peptidylprolyl isomerase D (cyclophilin D, encoded by Ppid) by administration of L-arginine (also in rats), caerulein, bile acid, or an AP-inducing diet. Parameters of pancreatitis, mitochondrial function, autophagy, ER stress, and lipid metabolism were measured in pancreatic tissue, acinar cells, and isolated mitochondria. Some mice with AP were given trehalose to enhance autophagic efficiency. Human pancreatitis tissues were analyzed by immunofluorescence. Mitochondrial dysfunction in pancreas of mice with AP was induced by either mitochondrial Ca2+ overload or through a Ca2+ overload-independent pathway that involved reduced activity of ATP synthase (80% inhibition in pancreatic mitochondria isolated from rats or mice given L-arginine). Both pathways were mediated by cyclophilin D and led to mitochondrial depolarization and fragmentation. Mitochondrial dysfunction caused pancreatic ER stress, impaired autophagy, and deregulation of lipid metabolism. These pathologic responses were abrogated in cyclophilin D-knockout mice. Administration of trehalose largely prevented trypsinogen activation, necrosis, and other parameters of pancreatic injury in mice with L-arginine AP. Tissues from patients with pancreatitis had markers of mitochondrial damage and impaired autophagy, compared with normal pancreas. In different animal models, we find a central role for mitochondrial dysfunction, and for impaired autophagy as its principal downstream effector, in development of AP. In particular, the pathway involving enhanced interaction of cyclophilin D with ATP synthase mediates L-arginine–induced pancreatitis, a model of severe AP the pathogenesis of which has remained unknown. Strategies to restore mitochondrial and/or autophagic function might be developed for treatment of AP.
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影响因子：
10.6
作者：
Kang, Rui;Chen, Ruochan;Zhang, Qiuhong;Hou, Wen;Wu, Sha;Cao, Lizhi;Huang, Jin;Yu, Yan;Fan, Xue-gong;Yan, Zhengwen;Sun, Xiaofang;Wang, Haichao;Wang, Qingde;Tsung, Allan;Billiar, Timothy R.;Zeh, Herbert J., III;Lotze, Michael T.;Tang, Daolin
通讯作者：
Tang, Daolin
DOI：
10.1152/ajpgi.00167.2006
发表时间：
2007-04-01
影响因子：
4.5
作者：
Dawra, Rajinder;Sharif, Rifat;Saluja, Ashok K.
通讯作者：
Saluja, Ashok K.
影响因子：
24.5
作者：
Noel P;Patel K;Durgampudi C;Trivedi RN;de Oliveira C;Crowell MD;Pannala R;Lee K;Brand R;Chennat J;Slivka A;Papachristou GI;Khalid A;Whitcomb DC;DeLany JP;Cline RA;Acharya C;Jaligama D;Murad FM;Yadav D;Navina S;Singh VP
通讯作者：
Singh VP
DOI：
10.1152/ajpgi.00471.2005
发表时间：
2006-08-01
影响因子：
4.5
作者：
Kubisch, Constanze H.;Sans, Maria Dolors;Logsdon, Craig D.
通讯作者：
Logsdon, Craig D.
影响因子：
15.9
作者：
Mareninova, Olga A.;Hermann, Kip;Gukovskaya, Anna S.
通讯作者：
Gukovskaya, Anna S.