Journal article
Loss of acinar cell VMP1 triggers spontaneous pancreatitis in mice
Autophagy, Vol.18(7), pp.1572-1582
07/03/2022
DOI: 10.1080/15548627.2021.1990672
PMCID: PMC9298442
PMID: 34709991
Abstract
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.
Details
- Title: Subtitle
- Loss of acinar cell VMP1 triggers spontaneous pancreatitis in mice
- Creators
- Shaogui Wang - University of Kansas Medical CenterXiaojuan Chao - University of Kansas Medical CenterXiaoxiao Jiang - University of Kansas Medical CenterTiantian Wang - Guangzhou University of Chinese MedicineYssa Rodriguez - University of Kansas Medical CenterLing Yang - University of IowaPal Pacher - National Institute on Alcohol Abuse and AlcoholismHong-Min Ni - University of Kansas Medical CenterWen-Xing Ding - University of Kansas Medical Center
- Resource Type
- Journal article
- Publication Details
- Autophagy, Vol.18(7), pp.1572-1582
- DOI
- 10.1080/15548627.2021.1990672
- PMID
- 34709991
- PMCID
- PMC9298442
- NLM abbreviation
- Autophagy
- ISSN
- 1554-8627
- eISSN
- 1554-8635
- Publisher
- Taylor & Francis
- Grant note
- DOI: 10.13039/100000049, name: National Institute on Aging, award: R01 AG072895; DOI: 10.13039/100000027, name: National Institute on Alcohol Abuse and Alcoholism, award: U01 AA024733; DOI: 10.13039/100000027, name: National Institute on Alcohol Abuse and Alcoholism, award: R37 AA020518; DOI: 10.13039/100000027, name: National Institute on Alcohol Abuse and Alcoholism, award: R21 AA026904; DOI: 10.13039/100000062, name: National institute of diabetes and digestive and kidney diseases, award: R01 DK 102142.
- Language
- English
- Date published
- 07/03/2022
- Academic Unit
- Molecular Physiology and Biophysics; Anatomy and Cell Biology; Fraternal Order of Eagles Diabetes Research Center
- Record Identifier
- 9984284348702771
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