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

作者：Su, Shenghan; Zhao, Qingrui; Dan, Lingfeng; Lin, Yuqing; Li, Xuebei; Zhang, Yunjin; Yang, Chunxiao; Dong, Yimeng; Li, Xiaohan; Regazzi, Romano; Sun, Changhao; Chu, Xia; Lu, Huimin^*

来源：Endocrinology and Metabolism, 2022, 37(6): 901-917.

DOI：10.3803/EnM.2022.1565

• Stearic acid
• Melatonin
• MicroRNAs
• Cellular senescence
• Mafa

Background: Chronic exposure to elevated levels of saturated fatty acids results in pancreatic (3-cell senescence. However, targets and effective agents for preventing stearic acid-induced (3-cell senescence are still lacking. Although melatonin administration can protect (3-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 (3-cells and elucidated the possible role of microRNAs in this process.Methods: (3-Cell senescence was identified by measuring the expression of senescence-related genes and senescence-associated (3-galactosidase staining. Gain-and loss-of-function approaches were used to investigate the involvement of microRNAs in stearic acid-evoked (3-cell senescence and dysfunction. Bioinformatics analyses and luciferase reporter activity assays were applied to pre-dict the direct targets of microRNAs.Results: 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 (3-TC6 cell lines. Melatonin effectively suppressed this process and reduced the levels of these two miRNAs. A remarkable reversibility of stearic acid-induced (3-cell senescence and dysfunction was observed after silenc-ing 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-5p-and miR-8114-transfected (3-cells.Conclusion: These data demonstrate that melatonin protects against stearic acid-induced (3-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 (3-cell dysfunction, but also points to melatonin as a promising drug to combat type 2 diabetes progression.

• 单位
  哈尔滨医科大学