Heparan sulfate proteoglycans in beta cells provide a critical link between endoplasmic reticulum stress, oxidative stress and type 2 diabetes.
Activating Transcription Factors
/ genetics
Animals
Cell Survival
/ drug effects
Cells, Cultured
Diabetes Mellitus, Type 2
/ metabolism
Disease Models, Animal
Endoplasmic Reticulum Stress
Glucuronidase
/ genetics
Heparan Sulfate Proteoglycans
/ metabolism
Heparitin Sulfate
/ metabolism
Humans
Hydrogen Peroxide
/ pharmacology
Insulin-Secreting Cells
/ cytology
Lactones
/ pharmacology
Mice
Mice, Inbred C57BL
Mice, Obese
Oxidative Stress
Sesquiterpenes
/ pharmacology
Transcription Factor CHOP
/ genetics
Up-Regulation
/ drug effects
Journal
PloS one
ISSN: 1932-6203
Titre abrégé: PLoS One
Pays: United States
ID NLM: 101285081
Informations de publication
Date de publication:
2021
2021
Historique:
received:
09
11
2020
accepted:
19
05
2021
entrez:
4
6
2021
pubmed:
5
6
2021
medline:
18
11
2021
Statut:
epublish
Résumé
Heparan sulfate proteoglycans (HSPGs) consist of a core protein with side chains of the glycosaminoglycan heparan sulfate (HS). We have previously identified (i) the HSPGs syndecan-1 (SDC1), and collagen type XVIII (COL18) inside mouse and human islet beta cells, and (ii) a critical role for HS in beta cell survival and protection from reactive oxygen species (ROS). The objective of this study was to investigate whether endoplasmic reticulum (ER) stress contributes to oxidative stress and type 2 diabetes (T2D) by depleting beta cell HSPGs/HS. A rapid loss of intra-islet/beta cell HSPGs, HS and heparanase (HPSE, an HS-degrading enzyme) accompanied upregulation of islet ER stress gene expression in both young T2D-prone db/db and Akita Ins2WT/C96Y mice. In MIN6 beta cells, HSPGs, HS and HPSE were reduced following treatment with pharmacological inducers of ER stress (thapsigargin or tunicamycin). Treatment of young db/db mice with Tauroursodeoxycholic acid (TUDCA), a chemical protein folding chaperone that relieves ER stress, improved glycemic control and increased intra-islet HSPG/HS. In vitro, HS replacement with heparin (a highly sulfated HS analogue) significantly increased the survival of wild-type and db/db beta cells and restored their resistance to hydrogen peroxide-induced death. We conclude that ER stress inhibits the synthesis/maturation of HSPG core proteins which are essential for HS assembly, thereby exacerbating oxidative stress and promoting beta cell failure. Diminished intracellular HSPGs/HS represent a previously unrecognized critical link bridging ER stress, oxidative stress and beta cell failure in T2D.
Identifiants
pubmed: 34086738
doi: 10.1371/journal.pone.0252607
pii: PONE-D-20-35185
pmc: PMC8177513
doi:
Substances chimiques
Activating Transcription Factors
0
Ddit3 protein, mouse
0
Heparan Sulfate Proteoglycans
0
Lactones
0
Sesquiterpenes
0
Transcription Factor CHOP
147336-12-7
thapsigargicin
67526-94-7
Heparitin Sulfate
9050-30-0
Hydrogen Peroxide
BBX060AN9V
heparanase
EC 3.2.1.-
Glucuronidase
EC 3.2.1.31
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e0252607Déclaration de conflit d'intérêts
The authors declare that no competing interests exist. The donation by Progen Pharmaceuticals Limited of PI-88 compound for in vitro studies does not alter our adherence to PLOS ONE policies on sharing data and materials.”
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