蛋白质毒性
未折叠蛋白反应
生物
胰腺炎
胰腺
杂合子优势
下调和上调
XBP1型
内分泌学
内科学
腺泡细胞
内质网
细胞生物学
蛋白质聚集
医学
RNA剪接
遗传学
基因
等位基因
核糖核酸
作者
Guoying Zhu,Steven J. Wilhelm,Leah G George,Brett M. Cassidy,Sammy Zino,Cliff J. Luke,Mina Hanna,Stephen Stone,Nhung Phan,Neel Matiwala,Samuel Ballentine,Mark E. Lowe,Xiangwei Xiao
出处
期刊:Gut
[BMJ]
日期:2023-01-11
卷期号:72 (7): 1340-1354
被引量:3
标识
DOI:10.1136/gutjnl-2022-327960
摘要
Objective Increasing evidence implicates mutation-induced protein misfolding and endoplasm reticulum (ER) stress in the pathophysiology of chronic pancreatitis (CP). The paucity of animal models harbouring genetic risk variants has hampered our understanding of how misfolded proteins trigger CP. We previously showed that pancreatic triglyceride lipase (PNLIP) p.T221M, a variant associated with steatorrhoea and possibly CP in humans, misfolds and elicits ER stress in vitro suggesting proteotoxicity as a potential disease mechanism. Our objective was to create a mouse model to determine if PNLIP p.T221M causes CP and to define the mechanism. Design We created a mouse model of Pnlip p.T221M and characterised the structural and biochemical changes in the pancreas aged 1–12 months. We used multiple methods including histochemistry, immunostaining, transmission electron microscopy, biochemical assays, immunoblotting and qPCR. Results We demonstrated the hallmarks of human CP in Pnlip p.T221M homozygous mice including progressive pancreatic atrophy, acinar cell loss, fibrosis, fatty change, immune cell infiltration and reduced exocrine function. Heterozygotes also developed CP although at a slower rate. Immunoblot showed that pancreatic PNLIP T221M misfolded as insoluble aggregates. The level of aggregates in homozygotes declined with age and was much lower in heterozygotes at all ages. The Pnlip p.T221M pancreas had increased ER stress evidenced by dilated ER, increased Hspa5 (BiP) mRNA abundance and a maladaptive unfolded protein response leading to upregulation of Ddit3 (CHOP), nuclear factor-κB and cell death. Conclusion Expression of PNLIP p.T221M in a preclinical mouse model results in CP caused by ER stress and proteotoxicity of misfolded mutant PNLIP.
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