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

• Published in: Endocrinology and metabolism (Seoul) 2022-12, Vol.37 (6), p.901-917
• Main Authors: 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
• Format: Article
• Language: English
• Subjects: Animals; Cellular Senescence; Diabetes Mellitus, Type 2 - metabolism; Insulin-Secreting Cells; Maf Transcription Factors, Large - metabolism; Maf Transcription Factors, Large - pharmacology; mafa; melatonin; Melatonin - metabolism; Melatonin - pharmacology; Mice; micrornas; MicroRNAs - genetics; MicroRNAs - metabolism; MicroRNAs - pharmacology; Original; stearic acid; Stearic Acids - metabolism; Stearic Acids - pharmacology
• ISSN: 2093-596X; 2093-5978
• DOI: 10.3803/EnM.2022.1565

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.