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Simvastatin induces autophagic flux to restore cerulein-impaired phagosome-lysosome fusion in acute pancreatitis.

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Citation: Biochimica et Biophysica Acta - Molecular Basis of Disease. 1865(11):165530, 2019 11 01.PMID: 31398467Institution: MedStar Washington Hospital CenterDepartment: Surgery/General SurgeryForm of publication: Journal ArticleMedline article type(s): Journal ArticleSubject headings: *Anticholesteremic Agents/tu [Therapeutic Use] | *Autophagy/de [Drug Effects] | *Lysosomes/de [Drug Effects] | *Pancreatitis/dt [Drug Therapy] | *Phagosomes/de [Drug Effects] | *Simvastatin/tu [Therapeutic Use] | Acute Disease | Animals | Anticholesteremic Agents/pd [Pharmacology] | Ceruletide/me [Metabolism] | Lysosomes/me [Metabolism] | Lysosomes/pa [Pathology] | Male | Membrane Fusion/de [Drug Effects] | Mice, Inbred C57BL | Pancreatitis/me [Metabolism] | Pancreatitis/pa [Pathology] | Phagosomes/me [Metabolism] | Phagosomes/pa [Pathology] | Simvastatin/pd [Pharmacology]Year: 2019 ISSN:

0925-4439

Name of journal: Biochimica et biophysica acta. Molecular basis of diseaseAbstract: BACKGROUND: During 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.CONCLUSION: Our findings reveal the novel role of simvastatin in enhancing autophagic flux to prevent pancreatic cell injury and pancreatitis.Copyright (c) 2019 Elsevier B.V. All rights reserved.METHODS: We examined whether simvastatin can protect cell death induced by cerulein and the mechanisms involved during acute pancreatitis. Mice were pretreated with DMSO or simvastatin (20mg/kg) for 24h followed by 7 hourly cerulein injections and sacrificed 1h after last injection to harvest blood and tissue for analysis.RESULTS: Pancreatic 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.All authors: Andres AM, de Freitas Germano J, Gaisano HY, Gottlieb RA, Gulla A, Hou J, Lugea A, Marek-Iannucci S, Pandol SJ, Piplani H, Saadaeijahromi H, Sharma A, Sin J, Song Y, Takahashi T, Waldron RT, Wu BOriginally published: Biochimica et Biophysica Acta - Molecular Basis of Disease. 1865(11):165530, 2019 Aug 06.Fiscal year: FY2020Digital Object Identifier:

https://dx.doi.org/10.1016/j.bbadis.2019.08.006

Date added to catalog: 2019-08-27

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Item type	Current library	Collection	Call number	Status	Date due	Barcode
Journal Article	MedStar Authors Catalog	Article	31398467	Available		31398467

BACKGROUND: During 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.

CONCLUSION: Our findings reveal the novel role of simvastatin in enhancing autophagic flux to prevent pancreatic cell injury and pancreatitis.

METHODS: We examined whether simvastatin can protect cell death induced by cerulein and the mechanisms involved during acute pancreatitis. Mice were pretreated with DMSO or simvastatin (20mg/kg) for 24h followed by 7 hourly cerulein injections and sacrificed 1h after last injection to harvest blood and tissue for analysis.

RESULTS: Pancreatic 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.

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