Protein Lysine Acetylation: An Unexpected Mediator in Pancreatitis
| Autor: | Fred S, Gorelick |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
PBS
phosphate-buffered saline CCK cholecystokinin IRE1 inositol-requiring enzyme 1 ATF activating transcription factor XBP1 x-box binding protein 1 AT-1 CER cerulein ER endoplasmic reticulum cDNA complementary DNA UPR unfolded protein response XBP1s x-box binding protein 1 spliced AP acute pancreatitis Tm tamoxifen Humans CP chronic pancreatitis Original Research KO knockout Lysine PERK protein kinase R-like ER kinase CHOP CCAAT/enhancer-binding protein homologous protein Acetylation WT wild-type mRNA messenger RNA Pancreatitis Unfolded Protein Response qPCR quantitative polymerase chain reaction ER Stress AT-1 acetyl-CoA transporter 1 SLC33A1 eIF2α elongation initiation factor 2α |
| Zdroj: | Cellular and Molecular Gastroenterology and Hepatology |
| ISSN: | 2352-345X |
| Popis: | 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. Graphical abstract |
| Databáze: | OpenAIRE |
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