Protection of Human Pancreatic Islets from Lipotoxicity by Modulation of the Translocon.
Protection of Human Pancreatic Islets from Lipotoxicity by Modulation of the Translocon.
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DOI：
10.1371/journal.pone.0148686
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发表时间：
2016
期刊：
影响因子：
3.7
通讯作者：
Madec AM
中科院分区：
文献类型：
--
作者：
Cassel R;Ducreux S;Alam MR;Dingreville F;Berlé C;Burda-Jacob K;Chauvin MA;Chikh K;Païta L;Al-Mawla R;Crola Da Silva C;Rieusset J;Thivolet C;Van Coppenolle F;Madec AM
2型糖尿病的特征是外周胰岛素抵抗和胰岛β细胞功能障碍。升高的游离脂肪酸(FFAs)可能损害β细胞的功能和质量(脂毒性)。钙稳态的改变可能与胰岛素释放缺陷有关。内质网(ER)是细胞内主要的钙储存区。脂毒性通过未知的内质网钙泄漏通道诱导内质网应激，同时导致内质网钙离子耗竭。这项研究的主要目的是首先确定这些通道之一，然后检查药物抑制内质网钙储备库耗竭后恢复β细胞功能(即胰岛素分泌)的机会。我们研究了内质网钙泄漏通道转位蛋白的功能及其在游离脂肪酸诱导的MIN6B1细胞和人胰岛改变中的作用。我们证明转运子在人β细胞中起着功能性的内质网钙泄漏通道的作用，分别使用该通道的阻断剂和开放剂--茴香霉素和嘌呤霉素(抗生素)。嘌呤霉素可引起明显的内质网钙释放，其作用可被苯异霉素预处理抑制。以棕榈酸酯处理为FFA模型，诱导β细胞内质网钙含量降低，诱导内质网应激，但不诱导细胞凋亡，葡萄糖诱导的胰岛素分泌减少。有趣的是，长期使用山奈素抑制转位可以预防棕榈酸酯引起的功能障碍，避免网状钙耗竭、内质网应激和恢复胰岛素的分泌。我们的结果首次提供了令人信服的证据，证明转位蛋白积极参与了棕榈酸酯诱导的内质网钙泄漏和胰岛β细胞胰岛素分泌减少。它的抑制作用减少了这些脂毒作用。综上所述，我们的数据表明TLC可能成为治疗2型糖尿病的新的潜在靶点。
Type 2 diabetes is characterized by peripheral insulin resistance and pancreatic beta cell dysfunction. Elevated free fatty acids (FFAs) may impair beta cell function and mass (lipotoxicity). Altered calcium homeostasis may be involved in defective insulin release. The endoplasmic reticulum (ER) is the major intracellular calcium store. Lipotoxicity induces ER stress and in parallel an ER calcium depletion through unknown ER calcium leak channels. The main purposes of this study is first to identify one of these channels and secondly, to check the opportunity to restore beta cells function (i.e., insulin secretion) after pharmacological inhibition of ER calcium store depletion. We investigated the functionality of translocon, an ER calcium leak channel and its involvement on FFAs-induced alterations in MIN6B1 cells and in human pancreatic islets. We evidenced that translocon acts as a functional ER calcium leak channel in human beta cells using anisomycin and puromycin (antibiotics), respectively blocker and opener of this channel. Puromycin induced a significant ER calcium release, inhibited by anisomycin pretreatment. Palmitate treatment was used as FFA model to induce a mild lipotoxic effect: ER calcium content was reduced, ER stress but not apoptosis were induced and glucose induced insulin secretion was decreased in our beta cells. Interestingly, translocon inhibition by chronic anisomycin treatment prevented dysfunctions induced by palmitate, avoiding reticular calcium depletion, ER stress and restoring insulin secretion. Our results provide for the first time compelling evidence that translocon actively participates to the palmitate-induced ER calcium leak and insulin secretion decrease in beta cells. Its inhibition reduces these lipotoxic effects. Taken together, our data indicate that TLC may be a new potential target for the treatment of type 2 diabetes.