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

<h4>Background</h4>For their functions of insulin biosynthesis and glucose- and fatty acid- mediated insulin secretion, Langerhans β-cells require an intracellular milieu rich in oxygen. This requirement makes β-cells, with their constitutively low antioxidative defense, susceptible to t...

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Autores principales:	Piyakarn Boontem, Tetsumori Yamashima
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/7c6a5a6df7a94280899a449cbdafb5b0
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spelling	oai:doaj.org-article:7c6a5a6df7a94280899a449cbdafb5b02021-12-02T20:05:59ZHydroxynonenal causes Langerhans cell degeneration in the pancreas of Japanese macaque monkeys.1932-620310.1371/journal.pone.0245702https://doaj.org/article/7c6a5a6df7a94280899a449cbdafb5b02021-01-01T00:00:00Zhttps://doi.org/10.1371/journal.pone.0245702https://doaj.org/toc/1932-6203<h4>Background</h4>For their functions of insulin biosynthesis and glucose- and fatty acid- mediated insulin secretion, 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 experimental systems, whether the oxidative stress due to excessive fatty acids plays a crucial role in the Langerhans cell degeneration in primates is still debated.<h4>Methods</h4>Focusing on Hsp70.1, which has dual functions as molecular chaperone and lysosomal stabilizer, the mechanism of lipotoxicity to Langerhans cells was studied using macaque monkeys after the consecutive injections of the lipid peroxidation product 'hydroxynonenal'. Based on the 'calpain-cathepsin hypothesis' formulated in 1998, calpain activation, Hsp70.1 cleavage, and lysosomal integrity were studied by immunofluorescence histochemistry, electron microscopy, and Western blotting.<h4>Results</h4>Light microscopy showed more abundant vacuole formation in the hydroxynonenal-treated islet cells than the control cells. Electron microscopy showed that vacuolar changes, which were identified as enlarged rough ER, 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 co-localization 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 expression of the hydroxynonenal receptor GPR109A.<h4>Conclusions</h4>Taken together, these data implicate hydroxynonenal in both oxidation of Hsp70.1 and activation of μ-calpain. The calpain-mediated cleavage of the carbonylated Hsp70.1, may cause lysosomal membrane rupture/permeabilization. The low defense of primate Langerhans cells against hydroxynonenal and peroxisomally-generated hydrogen peroxide, was presumably overwhelmed to facilitate cell degeneration.Piyakarn BoontemTetsumori YamashimaPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 16, Iss 11, p e0245702 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Piyakarn Boontem Tetsumori Yamashima Hydroxynonenal causes Langerhans cell degeneration in the pancreas of Japanese macaque monkeys.
description	<h4>Background</h4>For their functions of insulin biosynthesis and glucose- and fatty acid- mediated insulin secretion, 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 experimental systems, whether the oxidative stress due to excessive fatty acids plays a crucial role in the Langerhans cell degeneration in primates is still debated.<h4>Methods</h4>Focusing on Hsp70.1, which has dual functions as molecular chaperone and lysosomal stabilizer, the mechanism of lipotoxicity to Langerhans cells was studied using macaque monkeys after the consecutive injections of the lipid peroxidation product 'hydroxynonenal'. Based on the 'calpain-cathepsin hypothesis' formulated in 1998, calpain activation, Hsp70.1 cleavage, and lysosomal integrity were studied by immunofluorescence histochemistry, electron microscopy, and Western blotting.<h4>Results</h4>Light microscopy showed more abundant vacuole formation in the hydroxynonenal-treated islet cells than the control cells. Electron microscopy showed that vacuolar changes, which were identified as enlarged rough ER, 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 co-localization 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 expression of the hydroxynonenal receptor GPR109A.<h4>Conclusions</h4>Taken together, these data implicate hydroxynonenal in both oxidation of Hsp70.1 and activation of μ-calpain. The calpain-mediated cleavage of the carbonylated Hsp70.1, may cause lysosomal membrane rupture/permeabilization. The low defense of primate Langerhans cells against hydroxynonenal and peroxisomally-generated hydrogen peroxide, was presumably overwhelmed to facilitate cell degeneration.
format	article
author	Piyakarn Boontem Tetsumori Yamashima
author_facet	Piyakarn Boontem Tetsumori Yamashima
author_sort	Piyakarn Boontem
title	Hydroxynonenal causes Langerhans cell degeneration in the pancreas of Japanese macaque monkeys.
title_short	Hydroxynonenal causes Langerhans cell degeneration in the pancreas of Japanese macaque monkeys.
title_full	Hydroxynonenal causes Langerhans cell degeneration in the pancreas of Japanese macaque monkeys.
title_fullStr	Hydroxynonenal causes Langerhans cell degeneration in the pancreas of Japanese macaque monkeys.
title_full_unstemmed	Hydroxynonenal causes Langerhans cell degeneration in the pancreas of Japanese macaque monkeys.
title_sort	hydroxynonenal causes langerhans cell degeneration in the pancreas of japanese macaque monkeys.
publisher	Public Library of Science (PLoS)
publishDate	2021
url	https://doaj.org/article/7c6a5a6df7a94280899a449cbdafb5b0
work_keys_str_mv	AT piyakarnboontem hydroxynonenalcauseslangerhanscelldegenerationinthepancreasofjapanesemacaquemonkeys AT tetsumoriyamashima hydroxynonenalcauseslangerhanscelldegenerationinthepancreasofjapanesemacaquemonkeys
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Hydroxynonenal causes Langerhans cell degeneration in the pancreas of Japanese macaque monkeys.

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