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Phlda3 regulates beta cell survival during stress.
- Source :
-
Scientific reports [Sci Rep] 2019 Sep 06; Vol. 9 (1), pp. 12827. Date of Electronic Publication: 2019 Sep 06. - Publication Year :
- 2019
-
Abstract
- The loss of functional beta cell mass characterises all forms of diabetes. Beta cells are highly susceptible to stress, including cytokine, endoplasmic reticulum (ER) and oxidative stress. This study examined the role of pleckstrin homology-like, domain family A, member 3 (Phlda3) in beta cell survival under stress conditions and the regulatory basis. We found that the mRNA levels of Phlda3 were markedly upregulated in vivo in the islets of diabetic humans and mice. In vitro, exposure of MIN6 cells or islets to cytokines, palmitate, thapsigargin or ribose upregulated Phlda3 mRNA and protein levels, concurrent with the induction of ER stress (Ddit3 and Trb3) and antioxidant (Hmox1) genes. Furthermore, H <subscript>2</subscript> O <subscript>2</subscript> treatment markedly increased PHLDA3 immunostaining in human islets. Phlda3 expression was differentially regulated by adaptive (Xbp1) and apoptotic (Ddit3) unfolded protein response (UPR) mediators. siRNA-mediated knockdown of Xbp1 inhibited the induction of Phlda3 by cytokines and palmitate, whereas knockdown of Ddit3 upregulated Phlda3. Moreover, knockdown of Phlda3 potentiated cytokine-induced apoptosis in association with upregulation of inflammatory genes (iNos, IL1β and IκBα) and NFκB phosphorylation and downregulation of antioxidant (Gpx1 and Srxn1) and adaptive UPR (Xbp1, Hspa5 and Fkbp11) genes. Knockdown of Phlda3 also potentiated apoptosis under oxidative stress conditions induced by ribose treatment. These findings suggest that Phlda3 is crucial for beta cell survival under stress conditions. Phlda3 regulates the cytokine, oxidative and ER stress responses in beta cells via the repression of inflammatory gene expression and the maintenance of antioxidant and adaptive UPR gene expression. Phlda3 may promote beta cell survival in diabetes.
- Subjects :
- Animals
Antioxidants pharmacology
Cell Death drug effects
Cell Line
Cell Survival drug effects
Cytokines pharmacology
Cytoprotection drug effects
Endoplasmic Reticulum Chaperone BiP
Endoplasmic Reticulum Stress drug effects
Female
Humans
Insulin-Secreting Cells drug effects
Mice, Inbred C57BL
Mice, Inbred NOD
Models, Biological
NF-kappa B metabolism
Nuclear Proteins genetics
Oxidative Stress drug effects
Palmitic Acid pharmacology
RNA, Messenger genetics
RNA, Messenger metabolism
Thapsigargin pharmacology
Unfolded Protein Response drug effects
Up-Regulation drug effects
Up-Regulation genetics
X-Box Binding Protein 1 metabolism
Insulin-Secreting Cells cytology
Insulin-Secreting Cells metabolism
Nuclear Proteins metabolism
Stress, Physiological drug effects
Subjects
Details
- Language :
- English
- ISSN :
- 2045-2322
- Volume :
- 9
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Scientific reports
- Publication Type :
- Academic Journal
- Accession number :
- 31492921
- Full Text :
- https://doi.org/10.1038/s41598-019-49289-5