Human <i>CPA1</i> mutation causes digestive enzyme misfolding and chronic pancreatitis in mice

Hegyi, E; Sahin–Tóth, Miklós

doi:10.1136/gutjnl-2018-315994

Cited by 65 publications

(50 citation statements)

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“…This study showed that CPA1 N256K knock-in mice harboring the most frequent p.N256K human CPA1 mutation develop spontaneous and progressive CP and exhibit signs of ER stress in their pancreas. 56…”

Section: Mis-folding-associated Prss1 Mutationsmentioning

confidence: 99%

Genetics, Cell Biology, and Pathophysiology of Pancreatitis

et al. 2019

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Since the discovery of the first trypsinogen mutation in families with hereditary pancreatitis, pancreatic genetics has made rapid progress. The identification of mutations in genes involved in the digestive protease-antiprotease pathway has lent additional support to the notion that pancreatitis is a disease of autodigestion. Clinical and experimental observations have provided compelling evidence that premature intrapancreatic activation of digestive proteases is critical in pancreatitis onset. However, disease course and severity are mostly governed by inflammatory cells that drive local and systemic immune responses. In this article, we review the genetics, cell biology, and immunology of pancreatitis with a focus on protease activation pathways and other early events.

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Section: Mis-folding-associated Prss1 Mutationsmentioning

confidence: 99%

Genetics, Cell Biology, and Pathophysiology of Pancreatitis

et al. 2019

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“…Consistent with these data, it was recently shown that pancreatitis stimuli in human acinar cells reduces protective XBP1s signaling and in turn upregulates CHOP, cell damage, and activation of inflammatory signaling (12). In the past several years, mutations associated with digestive enzyme misfolding have been identified that, when introduced in mouse models, induce ER stress responses and exhibit spontaneous CP (13)(14)(15)(16)(17).…”

Section: Introductionmentioning

confidence: 99%

Deficient ER Acetyl-CoA Import in Acinar Cells Leads to Chronic Pancreatitis

Ddh

Deans

et al. 2020

Preprint

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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 play a central role in the development and progression of pancreatitis. A key event in this pathogenic response is a loss of the transcription factor spliced XBP1 (XBP1s) and activation of the PERK pathway. Less is known of the consequence of perturbing ER-associated post-translational protein modification during pancreatitis. Here we show that expression of the ER acetyl-CoA transporter AT-1, necessary for ER protein acetylation, lies downstream of XBP1s and is significantly downregulated during the onset of pancreatitis. Genetic deletion of AT-1 in acinar cells of adult pancreas induces chronic ER stress marked by activation of both the XBP1s and PERK pathways, leading to mild/moderate chronic pancreatitis evidenced by accumulation of intracellular trypsin, immune cell infiltration, and fibrosis, but little pancreatic degeneration. Two-day induction of acute on chronic pancreatitis in AT-1 acinar specific knockout mice results in a severe CP phenotype with pronounced pancreatic atrophy. These findings uncover a new layer of complexity of the pathological ER stress response and its impact on pancreatic disease. (189/200) ResultsRelationship of AT-1 expression, ER stress, and pancreatitis. It was previously reported that AT-1 expression is regulated downstream of the IRE1/XBP1s pathway (24). Consistent with this, AT-1 mRNA is significantly downregulated in acinar-specific Ela-Cre XBP1 -/pancreas ( Figure 1A), which display spontaneous pancreatic disease (unpublished results). XBP1s is upregulated in acinar cells during AP as a protective mechanism against ER stress-induced damage, then significantly decreases as the disease progresses (12). Accordingly, AT-1 mRNA is reduced by greater than 50% following cerulein induced AP (CER-AP) in WT mice ( Figure 1B, left), while AT-1 mRNA was decreased in 75% of WT mice subject to CER-CP ( Figure 1B, right). These results suggest that AT-1 loss during pancreatitis is secondary to the reduction in XBP1s activity and, based on the current results, likely exacerbates disease progression.Given the critical role of AT-1 in maintaining ER proteostasis and the well-defined relationship of elevated ER stress and pancreatitis, we examined whether dysregulation of AT-1 function itself would be sufficient to induce pancreatitis. AT-1 S113R/+ mice, which express a hypomorphic mutation that prevents AT-1 dimerization, have an approximate 50% reduction in ER acetyl-CoA transport activity (S113R homozygosity is embryonic lethal) (21).Notwithstanding the immune dysfunction reported in these mice, AT-1 S113R/+ acinar cells display widespread ER dilation and vacuolization, indicative of ER stress and cellular damage, which progresses over time ( Figure 1C). Likewise, AT-1 S113R/+ pancreas have increased collagen deposition ( Figure 1D), a marker of fibrosis.Generation of acinar-specific AT-1 KO ...

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“…1,2 Importantly, patients with CP are at a higher risk for pancreatic cancer, one of the most devastating diseases. The main clinical manifestations of CP are abdominal pain, indigestion, steatorrhea and diabetes.…”

Section: Introductionmentioning

confidence: 99%

Hic‐5 deficiency protects cerulein‐induced chronic pancreatitis via down‐regulation of the NF‐κB (p65)/IL‐6 signalling pathway

Chen

Tan

Qian

et al. 2019

J Cellular Molecular Medi

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Chronic pancreatitis (CP), characterized by pancreatic fibrosis, is a recurrent, progressive and irreversible disease. Activation of the pancreatic stellate cells (PSCs) is considered a core event in pancreatic fibrosis. In this study, we investigated the role of hydrogen peroxide-inducible clone-5 (Hic-5) in CP. Analysis of the human pancreatic tissue samples revealed that Hic-5 was overexpressed in patients with CP and was extremely low in healthy pancreas. Hic-5 was significant up-regulated in the activated primary PSCs independently from transforming growth factor beta stimulation. CP induced by cerulein injection was ameliorated in Hic-5 knockout (KO) mice, as shown by staining of tissue level. Simultaneously, the activation ability of the primary PSCs from Hic-5 KO mice was significantly attenuated. We also found that the Hic-5 up-regulation by cerulein activated the NF-κB (p65)/IL-6 signalling pathway and regulated the downstream extracellular matrix (ECM) genes such as α-SMA and Col1a1. Therefore, we determined whether suppressing NF-κB/p65 alleviated CP by treating mice with the NF-κB/p65 inhibitor triptolide in the cerulein-induced CP model and found that pancreatic fibrosis was alleviated by NF-κB/p65 inhibition.These findings provide evidence for Hic-5 as a therapeutic target that plays a crucial role in regulating PSCs activation and pancreatic fibrosis. K E Y W O R D S chronic pancreatitis, Hic-5, NF-κB, pancreatic stellate cells, triptolide | 1489 CHEN Et al. S U PP O RTI N G I N FO R M ATI O N Additional supporting information may be found online in the Supporting Information section. How to cite this article: Chen H, Tan P, Qian B, et al. Hic-5 deficiency protects cerulein-induced chronic pancreatitis via down-regulation of the NF-κB (p65)/IL-6 signalling pathway.

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Human CPA1 mutation causes digestive enzyme misfolding and chronic pancreatitis in mice

Abstract: The results offer categorical evidence that mutations elicit enzyme misfolding and cause chronic pancreatitis via an ER stress-related mechanism.

Cited by 65 publications

References 10 publications

Genetics, Cell Biology, and Pathophysiology of Pancreatitis

Genetics, Cell Biology, and Pathophysiology of Pancreatitis

Deficient ER Acetyl-CoA Import in Acinar Cells Leads to Chronic Pancreatitis

Hic‐5 deficiency protects cerulein‐induced chronic pancreatitis via down‐regulation of the NF‐κB (p65)/IL‐6 signalling pathway

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