Inhibition of miR-146a-5p and miR-8114 in Insulin-Secreting Cells Contributes to the Protection of Melatonin against Stearic Acid-Induced Cellular Senescence by Targeting Mafa.

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Version: author
License: CC BY-NC 4.0
Serval ID
serval:BIB_75304B1DDDAE
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Inhibition of miR-146a-5p and miR-8114 in Insulin-Secreting Cells Contributes to the Protection of Melatonin against Stearic Acid-Induced Cellular Senescence by Targeting Mafa.
Journal
Endocrinology and metabolism
Author(s)
Su S., Zhao Q., Dan L., Lin Y., Li X., Zhang Y., Yang C., Dong Y., Li X., Regazzi R., Sun C., Chu X., Lu H.
ISSN
2093-5978 (Electronic)
ISSN-L
2093-596X
Publication state
Published
Issued date
12/2022
Peer-reviewed
Oui
Volume
37
Number
6
Pages
901-917
Language
english
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
Abstract
Chronic exposure to elevated levels of saturated fatty acids results in pancreatic β-cell senescence. However, targets and effective agents for preventing stearic acid-induced β-cell senescence are still lacking. Although melatonin administration can protect β-cells against lipotoxicity through anti-senescence processes, the precise underlying mechanisms still need to be explored. Therefore, we investigated the anti-senescence effect of melatonin on stearic acid-treated mouse β-cells and elucidated the possible role of microRNAs in this process.
β-Cell senescence was identified by measuring the expression of senescence-related genes and senescence-associated β-galactosidase staining. Gain- and loss-of-function approaches were used to investigate the involvement of microRNAs in stearic acid-evoked β-cell senescence and dysfunction. Bioinformatics analyses and luciferase reporter activity assays were applied to predict the direct targets of microRNAs.
Long-term exposure to a high concentration of stearic acid-induced senescence and upregulated miR-146a-5p and miR- 8114 expression in both mouse islets and β-TC6 cell lines. Melatonin effectively suppressed this process and reduced the levels of these two miRNAs. A remarkable reversibility of stearic acid-induced β-cell senescence and dysfunction was observed after silencing miR-146a-5p and miR-8114. Moreover, V-maf musculoaponeurotic fibrosarcoma oncogene homolog A (Mafa) was verified as a direct target of miR-146a-5p and miR-8114. Melatonin also significantly ameliorated senescence and dysfunction in miR-146a-5pand miR-8114-transfected β-cells.
These data demonstrate that melatonin protects against stearic acid-induced β-cell senescence by inhibiting miR-146a- 5p and miR-8114 and upregulating Mafa expression. This not only provides novel targets for preventing stearic acid-induced β-cell dysfunction, but also points to melatonin as a promising drug to combat type 2 diabetes progression.
Keywords
Mice, Animals, Insulin-Secreting Cells, Melatonin/pharmacology, Melatonin/metabolism, Diabetes Mellitus, Type 2/metabolism, MicroRNAs/genetics, MicroRNAs/metabolism, MicroRNAs/pharmacology, Cellular Senescence, Stearic Acids/pharmacology, Stearic Acids/metabolism, Maf Transcription Factors, Large/metabolism, Maf Transcription Factors, Large/pharmacology, Cellular senescence, Mafa, Melatonin, MicroRNAs, Stearic acid
Pubmed
Open Access
Yes
Create date
12/12/2022 9:11
Last modification date
18/01/2023 7:51
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