Center for Exocrine Disorders, Department of Molecular and Cell Biology, Boston University, Henry M. Goldman School of Dental Medicine, Boston, Massachusetts.
Department of Surgery, University of California Los Angeles, Los Angeles, California.
Am J Physiol Gastrointest Liver Physiol. 2020 Apr 1;318(4):G694-G704. doi: 10.1152/ajpgi.00007.2020. Epub 2020 Mar 2.
Alcoholic pancreatitis is a multifactorial, progressive, inflammatory disorder of the pancreas. Alcohol initiates pancreatitis and promotes its progression in the context of genetic susceptibility and/or other environmental risk factors such as smoking. Genetic mutations can cause digestive enzyme misfolding, which induces endoplasmic reticulum (ER) stress and elicits pancreatitis. Here, we tested the hypothesis that alcohol synergizes with misfolding in promoting ER stress and thereby accelerates chronic pancreatitis progression. To this end, we fed an ethanol-containing diet to mice, which carry the human p.N256K mutation and develop spontaneous chronic pancreatitis. Inexplicably, mice suffered generalized seizures after 2-3 wk of ethanol feeding, which resulted in high mortality and the early termination of the study. Analysis of mice euthanized after 3-3.5 wk of ethanol feeding revealed more severe chronic pancreatitis associated with significantly increased [ER chaperone immunoglobulin heavy chain-binding protein (BiP)] mRNA levels when compared with mice on a control liquid diet. In contrast, ethanol feeding of C57BL/6N mice for 4 wk increased levels to a lesser degree and caused no pancreatitis. We conclude that ethanol feeding synergizes with the misfolding CPA1 mutant in promoting ER stress and thereby accelerates progression of chronic pancreatitis in mice. Alcoholic pancreatitis is a multifactorial, progressive, inflammatory disorder of the pancreas. This study demonstrates that alcohol synergizes with digestive enzyme misfolding in promoting endoplasmic reticulum stress and thereby accelerates progression of chronic pancreatitis.
酒精性胰腺炎是一种多因素、进行性、胰腺炎症性疾病。在遗传易感性和/或其他环境风险因素（如吸烟）的背景下，酒精引发胰腺炎，并促进其进展。遗传突变可导致消化酶错误折叠，从而诱导内质网（ER）应激并引发胰腺炎。在这里，我们测试了这样一个假设，即酒精与错误折叠协同作用，促进 ER 应激，从而加速慢性胰腺炎的进展。为此，我们用含酒精的饮食喂养携带人 p.N256K 突变并自发发展为慢性胰腺炎的小鼠。令人费解的是，这些小鼠在接受酒精喂养 2-3 周后会出现全身性癫痫发作，这导致了高死亡率，并使研究提前终止。对接受酒精喂养 3-3.5 周后安乐死的小鼠进行分析，结果显示与接受对照液体饮食的小鼠相比，这些小鼠的慢性胰腺炎更严重，与 ER 伴侣免疫球蛋白重链结合蛋白（BiP）mRNA 水平显著增加有关。相比之下，用含酒精的饮食喂养 C57BL/6N 小鼠 4 周只会导致 BiP 水平的适度增加，而不会引起胰腺炎。我们得出结论，酒精喂养与错误折叠的 CPA1 突变协同作用，促进 ER 应激，从而加速了 小鼠慢性胰腺炎的进展。酒精性胰腺炎是一种多因素、进行性、胰腺炎症性疾病。本研究表明，酒精与消化酶错误折叠协同作用，促进内质网应激，从而加速慢性胰腺炎的进展。
