Dataset Information

Loss of acinar cell IKK? triggers spontaneous pancreatitis in mice.

ABSTRACT: Chronic pancreatitis is an inflammatory disease that causes progressive destruction of pancreatic acinar cells and, ultimately, loss of pancreatic function. We investigated the role of I?B kinase ? (IKK?) in pancreatic homeostasis. Pancreas-specific ablation of IKK? (Ikk?(?pan)) caused spontaneous and progressive acinar cell vacuolization and death, interstitial fibrosis, inflammation, and circulatory release of pancreatic enzymes, clinical signs resembling those of human chronic pancreatitis. Loss of pancreatic IKK? causes defective autophagic protein degradation, leading to accumulation of p62-mediated protein aggregates and enhanced oxidative and ER stress in acinar cells, but none of these effects is related to NF-?B. Pancreas-specific p62 ablation prevented ER and oxidative stresses and attenuated pancreatitis in Ikk?(?pan) mice, suggesting that cellular stress induced by p62 aggregates promotes development of pancreatitis. Importantly, downregulation of IKK? and accumulation of p62 aggregates were also observed in chronic human pancreatitis. Our studies demonstrate that IKK?, which may control autophagic protein degradation through its interaction with ATG16L2, plays a critical role in maintaining pancreatic acinar cell homeostasis, whose dysregulation promotes pancreatitis through p62 aggregate accumulation.

SUBMITTER: Li N

PROVIDER: S-EPMC3635720 | biostudies-literature | 2013 May

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Loss of acinar cell IKKα triggers spontaneous pancreatitis in mice.

Li Ning N Wu Xuefeng X Holzer Ryan G RG Lee Jun-Hee JH Todoric Jelena J Park Eek-Joong EJ Ogata Hisanobu H Gukovskaya Anna S AS Gukovsky Ilya I Pizzo Donald P DP VandenBerg Scott S Tarin David D Atay Ciǧdem C Arkan Melek C MC Deerinck Thomas J TJ Moscat Jorge J Diaz-Meco Maria M Dawson David D Erkan Mert M Kleeff Jörg J Karin Michael M

The Journal of clinical investigation 20130408 5

Chronic pancreatitis is an inflammatory disease that causes progressive destruction of pancreatic acinar cells and, ultimately, loss of pancreatic function. We investigated the role of IκB kinase α (IKKα) in pancreatic homeostasis. Pancreas-specific ablation of IKKα (Ikkα(Δpan)) caused spontaneous and progressive acinar cell vacuolization and death, interstitial fibrosis, inflammation, and circulatory release of pancreatic enzymes, clinical signs resembling those of human chronic pancreatitis. L ...[more]

PMID: 23563314

Similar Datasets

Project description:The pathogenesis of pancreatitis has been linked to disruption of organelle homeostasis including macroautophagy/autophagy dysfunction and endoplasmic reticulum (ER) stress. However, the direct impact of aberrant organelle function on pancreatitis initiation and progression is largely unknown. Recently an ER membrane protein, VMP1 (vacuole membrane protein 1), has been reported to play a crucial role in autophagosome formation. Notably, we found that VMP1 is downregulated in both human chronic pancreatitis (CP) and experimental mouse acute pancreatitis (AP). Pancreatic acinar cell-specific vmp1 deletion promotes inflammation, acinar-to-ductal metaplasia, and fibrosis in mice, sharing histological similarities with human CP. Mechanistically, loss of pancreatic VMP1 leads to defective autophagic degradation and ER stress as well as activation of the NFE2L2/Nrf2 pathway. Genetic ablation of NFE2L2 attenuated pancreatitis in VMP1-deficient mice. Our data highlight the importance of VMP1 in modulating an integrated organelle stress response and its functional role in maintaining pancreas homeostasis in the context of CP.Abbreviations: AMY: amylase; ADM: acinar-to-ductal metaplasia; AP: acute pancreatitis; CASP3: caspase 3; CP: chronic pancreatitis; DDIT3/CHOP: DNA damage inducible transcript 3; DKO, double knockout; ER: endoplasmic reticulum; GCLC: glutamate-cysteine ligase catalytic subunit; GCLM: glutamate-cysteine ligase modifier subunit; HSPA5/BIP: heat shock protein family A (Hsp70) member 5; KO: knockout; KRT19/CK19: keratin 19; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MPO: myeloperoxidase; NFE2L2/NRF2: nuclear factor, erythroid 2 like 2; ND: normal donor; NQO1: NAD(P)H quinone dehydrogenase 1; PCNA: proliferating cell nuclear antigen; RIPA: radio-immunoprecipitation; SQSTM1/p62: sequestosome 1; SOX9: SRY-box transcription factor 9; TAP: trypsinogen activation peptide; TFEB: transcription factor EB; TUNEL: terminal deoxynucleotidyl transferase dUTP nick end labeling; UB: ubiquitin; VMP1: vacuole membrane protein 1; XBP1: X-box binding protein 1; YAP1, Yes1 associated transcriptional regulator; ZG: zymogen granule.

Dataset Information

Loss of acinar cell IKK? triggers spontaneous pancreatitis in mice.

Publications

Loss of acinar cell IKKα triggers spontaneous pancreatitis in mice.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets