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Loss of acinar cell VMP1 triggers spontaneous pancreatitis in mice
Shaogui Wang1,2, Xiaojuan Chao1, Xiaoxiao Jiang1
1Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS, USA.
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.
Insights
Vacuole membrane protein 1 (VMP1) downregulation exacerbates pancreatitis by impairing autophagy and causing endoplasmic reticulum (ER) stress. Restoring NFE2L2/Nrf2 signaling alleviates pancreatitis in VMP1-deficient models.
Area of Science:
- Cell Biology
- Gastroenterology
- Pathology
Background:
- Pancreatitis pathogenesis involves organelle dysfunction, including autophagy defects and endoplasmic reticulum (ER) stress.
- The specific role of aberrant organelle function in initiating and progressing pancreatitis remains largely undefined.
- Vacuole membrane protein 1 (VMP1), an ER protein, is critical for autophagosome formation.
Purpose of the Study:
- To investigate the direct impact of vacuole membrane protein 1 (VMP1) dysfunction on pancreatitis.
- To elucidate the mechanistic link between VMP1, organelle homeostasis, and pancreatitis progression.
- To evaluate the therapeutic potential of targeting the NFE2L2/Nrf2 pathway in VMP1-related pancreatitis.
Main Methods:
- Analysis of VMP1 expression in human chronic pancreatitis (CP) and experimental mouse acute pancreatitis (AP).
- Generation of pancreatic acinar cell-specific vmp1 knockout mice to assess its role in vivo.
- Assessment of autophagic degradation, ER stress markers, and NFE2L2/Nrf2 pathway activation.
- Genetic ablation of NFE2L2 in VMP1-deficient mice to determine its role in pancreatitis attenuation.
Main Results:
- VMP1 was found to be downregulated in both human CP and experimental AP.
- Pancreatic acinar cell-specific vmp1 deletion induced inflammation, acinar-to-ductal metaplasia, and fibrosis, mimicking human CP.
- Loss of VMP1 resulted in impaired autophagic degradation, increased ER stress, and activation of the NFE2L2/Nrf2 pathway.
- Genetic deletion of NFE2L2 significantly attenuated pancreatitis in VMP1-deficient mice.
Conclusions:
- VMP1 plays a critical role in maintaining pancreas homeostasis by regulating organelle stress responses.
- VMP1 downregulation contributes to pancreatitis initiation and progression through defective autophagy and ER stress.
- The NFE2L2/Nrf2 pathway is a key mediator of pancreatitis in the context of VMP1 deficiency, suggesting a potential therapeutic target.
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