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Defective Trafficking Of Lysosomal Hydrolases Causes Spontaneous Pancreatitis

Pancreatology(2016)

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Abstract
progeria among other disorders.Little if anything is known about the role of lamins in the exocrine pancreas although patients with partial lipodystrophy, resulting from LMNA mutation, have an increased susceptibility to pancreatitis (Oral et al, manuscript in preparation).We tested the hypothesis that lamin A/C plays a role in normal acinar cell homeostasis.Methods: Pancreatic acinar-specific lamin A/C deficient C57BL/6 (lamin KO) mice were generated by crossing floxed LMNA mice with elastase-CreERT mice.Age and sex matched Cre-and floxed Cre+ littermates were injected daily for 3 days with tamoxifen to induce recombination in pancreatic acinar cells.Mice were harvested 72 and 144 hours after the 3-day induction of Cre and analyzed using histological, biochemical, and ultrastructural tools.Pancreatic injury was assessed by acinar cell degranulation, presence of CD45+ cells, edema, ultrastructural abnormalities, and keratin 19 expression.Acinar cell apoptosis was determined using TUNEL staining, and cleaved-caspase 3 staining and immunoblot analysis.Targeted studies and unbiased transcriptomic and proteomic approaches were used to identify pathways that are dysregulated in lamin A/C-deficient acinar cells.Results: Pancreatic acinar cell-specific lamin KO mice develop spontaneous pancreatitis 144 hours, but not 72 hours, after Cre induction and lamin A/C ablation.Knockout acinar cells become degranulated and express high levels of keratin 19, suggesting acinar to ductal metaplasia.Pancreata from lamin KO mice have higher levels of CD45+ inflammatory cells, edema, and vacuolization.An average of 18% of the cells in the exocrine pancreas appeared apoptotic, compared to 1% in control pancreata (p=0.015).Known downstream targets of the MAPK cascade such as ATF2 and ATF4 were induced in lamin KO mice, consistent with findings from cardiac laminopathy mice.Endoplasmic reticulum (ER) stress-related markers also become markedly elevated.Conclusion: Lamin A/C deletion in pancreatic acinar cells leads to ER stress and spontaneous pancreatitis, acinar cell apoptosis and activation of MAPK signaling.This newly discovered role of lamin A/C in regulating pancreatic acinar cell homeostasis suggests that patients with LMNA mutation may have increased susceptibility to pancreatitis, consistent with observations from patients with partial lipodystrophy.
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Key words
lysosomal hydrolases,spontaneous pancreatitis,defective trafficking
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