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Deficient Endoplasmic Reticulum Acetyl-CoA Import in Pancreatic Acinar Cells Leads to Chronic Pancreatitis
Cellular and Molecular Gastroenterology and Hepatology ( IF 7.2 ) Pub Date : 2020-10-17 , DOI: 10.1016/j.jcmgh.2020.10.008
Michelle M Cooley 1 , Diana D H Thomas 1 , Kali Deans 1 , Yajing Peng 2 , Aurelia Lugea 3 , Stephen J Pandol 3 , Luigi Puglielli 4 , Guy E Groblewski 1
Affiliation  

Background & Aims

Maintaining endoplasmic reticulum (ER) proteostasis is essential for pancreatic acinar cell function. Under conditions of severe ER stress, activation of pathogenic unfolded protein response pathways plays a central role in the development and progression of pancreatitis. Less is known, however, of the consequence of perturbing ER-associated post-translational protein modifications on pancreatic outcomes. Here, we examined the role of the ER acetyl-CoA transporter AT-1 on pancreatic homeostasis.

Methods

We used an AT-1S113R/+ hypomorphic mouse model, and generated an inducible, acinar-specific, AT-1 knockout mouse model, and performed histologic and biochemical analyses to probe the effect of AT-1 loss on acinar cell physiology.

Results

We found that AT-1 expression is down-regulated significantly during both acute and chronic pancreatitis. Furthermore, acinar-specific deletion of AT-1 in acinar cells induces chronic ER stress marked by activation of both the spliced x-box binding protein 1 and protein kinase R-like ER kinase pathways, leading to spontaneous mild/moderate chronic pancreatitis evidenced by accumulation of intracellular trypsin, immune cell infiltration, and fibrosis. Induction of acute-on-chronic pancreatitis in the AT-1 model led to acinar cell loss and glad atrophy.

Conclusions

These results indicate a key role for AT-1 in pancreatic acinar cell homeostasis, the unfolded protein response, and that perturbations in AT-1 function leads to pancreatic disease.



中文翻译:

胰腺腺泡细胞中内质网乙酰辅酶A导入不足导致慢性胰腺炎

背景与目标

维持内质网 (ER) 蛋白质稳态对于胰腺腺泡细胞功能至关重要。在严重的内质网应激条件下,致病性未折叠蛋白反应通路的激活在胰腺炎的发展和进展中起着核心作用。然而,关于扰乱 ER 相关的翻译后蛋白质修饰对胰腺结果的后果知之甚少。在这里,我们检查了 ER 乙酰辅酶 A 转运蛋白 AT-1 对胰腺稳态的作用。

方法

我们使用了一个 AT-1 S113R/+ 亚形小鼠模型,并生成了一个可诱导的、腺泡特异性的、AT-1 敲除小鼠模型,并进行了组织学和生化分析来探讨 AT-1 丢失对腺泡细胞生理学的影响。

结果

我们发现 AT-1 表达在急性和慢性胰腺炎期间均显着下调。此外,腺泡细胞中 AT-1 的腺泡特异性缺失诱导慢性 ER 应激,其特征是激活剪接的 x-box 结合蛋白 1 和蛋白激酶 R 样 ER 激酶途径,导致自发性轻度/中度慢性胰腺炎。细胞内胰蛋白酶的积累、免疫细胞浸润和纤维化。在 AT-1 模型中诱导急性-慢性胰腺炎导致腺泡细胞丢失和萎缩。

结论

这些结果表明 AT-1 在胰腺腺泡细胞稳态、未折叠蛋白反应中的关键作用,以及 AT-1 功能的扰动导致胰腺疾病。

更新日期:2020-10-17
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