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Hydroxynonenal causes Langerhans cell degeneration in the pancreas of Japanese macaque monkeys

Piyakarn Boontem, Tetsumori Yamashima
doi: https://doi.org/10.1101/2021.01.07.425690
Piyakarn Boontem
1Departments of Cell Metabolism and Nutrition
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Tetsumori Yamashima
1Departments of Cell Metabolism and Nutrition
2Psychiatry and Behavioral Science
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  • For correspondence: yamashima215@gmail.com
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Abstract

Background For their functions of insulin biosynthesis and glucose- and fatty acid- induced insulin secretion, the Langerhans β-cells require an intracellular milieu rich in oxygen. This requirement makes β-cells, with their constitutively low antioxidative defense, susceptible to the oxidative stress. Although much progress has been made in identifying its molecular basis in the experimental systems, whether the oxidative stress due to excessive fatty acids plays a crucial role in the Langerhans degeneration in primates is still debated.

Methods Focusing on Hsp70.1, which has dual functions as a molecular chaperone and lysosomal stabilizer, the mechanism of lipotoxicity to the Langerhans islet cells was studied using Japanese macaque monkeys (Macaca fuscata) after the consecutive injections of the lipid peroxidation product hydroxynonenal. Based on the ‘calpain-cathepsin hypothesis’ of ischemic neuronal death formulated in 1998, calpain activation, Hsp70.1 cleavage, and lysosomal integrity were studied by immunofluorescence histochemistry, electron microscopy and Western blotting.

Results Light microscopy showed higher vacuole formation in the treated islet cells than in the control cells. Electron microscopy showed that vacuolar changes that were identified as enlarged rough endoplasmic reticula occurred mainly in β-cells followed by δ-cells. Intriguingly, both cell types showed a marked decrease in insulin and somatostatin granules. Furthermore, they exhibited marked increases in peroxisomes, autophagosomes/autolysosomes, lysosomal and peroxisomal membrane rupture/permeabilization, and mitochondrial degeneration. Disrupted peroxisomes were often localized in the close vicinity of degenerating mitochondria or autolysosomes. Immunofluorescence histochemical analysis showed an increased colocalization of activated μ-calpain and Hsp70.1 with the extralysosomal release of cathepsin B. Western blotting showed increases in μ-calpain activation, Hsp70.1 cleavage, and hydroxynonenal receptor GPR109A expression.

Conclusions Taken together, these data implicate hydroxynonenal in both the carbonylation of Hsp70.1 and the activation of μ-calpain. The calpain-mediated cleavage of the carbonyl group on Hsp70.1 after the hydroxynonenal-mediated carbonylation of Hsp70.1, may cause lysosomal membrane rupture/permeabilization. The low defense of primate Langerhans cells against exogenous hydroxynonenal and peroxisomally-generated hydrogen peroxide, was presumably overwhelmed to facilitate cell degeneration.

  • LIST OF ABBREVIATIONS

    ER
    endoplasmic reticulum
    Hsp70.1
    heat-shock protein 70.1
    H2O2
    hydrogen peroxide
    OH•
    hydroxyl radicals
    NEFAs
    nonesterified fatty acids
    ROS
    reactive oxygen species
    O2•−
    superoxide radicals
  • Copyright 
    The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license.
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    Posted January 07, 2021.
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    Hydroxynonenal causes Langerhans cell degeneration in the pancreas of Japanese macaque monkeys
    Piyakarn Boontem, Tetsumori Yamashima
    bioRxiv 2021.01.07.425690; doi: https://doi.org/10.1101/2021.01.07.425690
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    Hydroxynonenal causes Langerhans cell degeneration in the pancreas of Japanese macaque monkeys
    Piyakarn Boontem, Tetsumori Yamashima
    bioRxiv 2021.01.07.425690; doi: https://doi.org/10.1101/2021.01.07.425690

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