ArticleBiochimica et biophysica acta. Molecular basis of disease2019
Simvastatin induces autophagic flux to restore cerulein-impaired phagosome-lysosome fusion in acute pancreatitis.
Article in Biochimica et biophysica acta. Molecular basis of disease, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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Who cites it
20 citing papers in PubMed, 40 citations in OpenAlex.
- Reprogramming of cholesterol sensing in epithelial cells supports pancreatic inflammation.Molecular metabolism · 2026Article
- Mitochondrial dysfunction as a bridge to pathology in acute pancreatitis: From molecular insights to novel therapeutic strategies.World journal of gastroenterology · 2025Review
- L-arginine-induced chronic pancreatitis in mice: Evaluating effects of pirfenidone and simvastatin.World journal of gastrointestinal pharmacology and therapeutics · 2025Article
- Dysfunction of Autophagy in Adipose Tissue Macrophages Regulated via FoxO1 in Obesity-Related Severe Acute Pancreatitis.International journal of molecular sciences · 2025Article
- Gut microbiota analysis and LC-MS-based metabolomics to investigate AMPK/NF-κB regulated by Clostridium butyricum in the treatment of acute pancreatitis.Journal of translational medicine · 2024Article
- Molecular mechanism and potential role of mitophagy in acute pancreatitis.Molecular medicine (Cambridge, Mass.) · 2024Review
- Mitochondrial calcium uniporter promotes mitophagy by regulating the PINK1/Parkin pathway in caerulein‑treated pancreatic ductal epithelial cellsExperimental and therapeutic medicine · 2024Article
- Isorhamnetin Alleviates Mitochondrial Injury in Severe Acute Pancreatitis via Modulation of KDM5B/HtrA2 Signaling Pathway.International journal of molecular sciences · 2024Article
- Mitochondrial dysfunction in pancreatic acinar cells: mechanisms and therapeutic strategies in acute pancreatitis.Frontiers in immunology · 2024Review
- Activation of AMPK ameliorates acute severe pancreatitis by suppressing pancreatic acinar cell necroptosis in obese mice models.Cell death discovery · 2023Article
- Modulation of autophagy as a therapeutic strategy forFrontiers in cellular and infection microbiology · 2022Review
- Idiopathic chronic pancreatitis: Beyond antioxidants.World journal of gastroenterology · 2021Article
- Dysregulation of mannose-6-phosphate-dependent cholesterol homeostasis in acinar cells mediates pancreatitis.The Journal of clinical investigation · 2021Article
- Pancreas-specific deletion of protein kinase D attenuates inflammation, necrosis, and severity of acute pancreatitis.Biochimica et biophysica acta. Molecular basis of disease · 2021Article
- Review
- The Remedial Potential of Lycopene in Pancreatitis through Regulation of Autophagy.International journal of molecular sciences · 2020Review
- Docosahexaenoic acid inhibits zymogen activation by suppressing vacuolar ATPase activation in cerulein-stimulated pancreatic acinar cells.Genes & nutrition · 2020Article
- BRD4 Inhibition Protects Against Acute Pancreatitis Through Restoring Impaired Autophagic Flux.Frontiers in pharmacology · 2020Article
- Article
- Autophagy and Glycometabolic Reprograming in the Malignant Progression of Lung Cancer: A Review.Technology in cancer research & treatmentReview
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Authors and funding
17 authors at 5 institutions in 4 countries.
Funding
Abstract
backgroundDuring pancreatitis, autophagy is activated, but lysosomal degradation of dysfunctional organelles including mitochondria is impaired, resulting in acinar cell death. Retrospective cohort analyses demonstrated an association between simvastatin use and decreased acute pancreatitis incidence.
methodsWe examined whether simvastatin can protect cell death induced by cerulein and the mechanisms involved during acute pancreatitis. Mice were pretreated with DMSO or simvastatin (20 mg/kg) for 24 h followed by 7 hourly cerulein injections and sacrificed 1 h after last injection to harvest blood and tissue for analysis.
resultsPancreatic histopathology revealed that simvastatin reduced necrotic cell death, inflammatory cell infiltration and edema. We found that cerulein triggered mitophagy with autophagosome formation in acinar cells. However, autophagosome-lysosome fusion was impaired due to altered levels of LAMP-1, AMPK and ULK-1, resulting in autophagosome accumulation (incomplete autophagy). Simvastatin abrogated these effects by upregulating LAMP-1 and activating AMPK which phosphorylated ULK-1, resulting in increased formation of functional autolysosomes. In contrast, autophagosomes accumulated in control group during pancreatitis. The effects of simvastatin to promote autophagic flux were inhibited by chloroquine. Mitochondria from simvastatin-treated mice were resistant to calcium overload compared to control, suggesting that simvastatin induced mitochondrial quality control to eliminate susceptible mitochondria. Clinical specimens showed a significant increase in cell-free mtDNA in plasma during pancreatitis compared to normal controls. Furthermore, genetic deletion of parkin abrogated the benefits of simvastatin.
conclusionOur findings reveal the novel role of simvastatin in enhancing autophagic flux to prevent pancreatic cell injury and pancreatitis.
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