Inhibition of lncRNA TCONS_00077866 Ameliorates the High Stearic Acid Diet-Induced Mouse Pancreatic β-Cell Inflammatory Response by Increasing miR-297b-5p to Downregulate SAA3 Expression

• Published in: Diabetes (New York, N.Y.) Vol. 70; no. 10; pp. 2275 - 2288
• Main Authors: Lu, Huimin, Guo, Rui, Zhang, Yunjin, Su, Shenghan, Zhao, Qingrui, Yu, Yue, Shi, Hongbo, Sun, Haoran, Zhang, Yongjian, Li, Shenglong, Shi, Dan, Chu, Xia, Sun, Changhao
• Format: Journal Article
• Language: English
• Published: United States American Diabetes Association 01-10-2021
• Subjects: Amyloid; Animals; Beta cells; Cells, Cultured; Diabetes; Diabetes mellitus (non-insulin dependent); Diabetes Mellitus, Type 2 - genetics; Diabetes Mellitus, Type 2 - metabolism; Diabetes Mellitus, Type 2 - pathology; Diabetes Mellitus, Type 2 - prevention & control; Diet, High-Fat - adverse effects; Down-Regulation - drug effects; Gene Expression Regulation - drug effects; HEK293 Cells; High fat diet; Humans; Inflammation; Inflammation - etiology; Inflammation - genetics; Inflammation - pathology; Inflammation - prevention & control; Insulin; Insulin secretion; Insulin Secretion - drug effects; Insulin-Secreting Cells - drug effects; Insulin-Secreting Cells - metabolism; Insulin-Secreting Cells - pathology; Male; Mice; Mice, Inbred C57BL; MicroRNAs - genetics; Molecular modelling; mRNA; Next-generation sequencing; Palmitic Acid - adverse effects; Palmitic Acid - pharmacology; Pancreas; Pancreatitis - etiology; Pancreatitis - genetics; Pancreatitis - pathology; Pancreatitis - prevention & control; Regulatory sequences; RNA, Long Noncoding - antagonists & inhibitors; RNA, Long Noncoding - genetics; RNA, Small Interfering - pharmacology; Sequence analysis; Serum Amyloid A Protein - genetics; Stearic acid; Stearic Acids - adverse effects; Stearic Acids - pharmacology
• ISSN: 0012-1797; 1939-327X
• DOI: 10.2337/db20-1079

Long-term consumption of a high-fat diet increases the circulating concentration of stearic acid (SA), which has a potent toxic effect on β-cells, but the underlying molecular mechanisms of this action have not been fully elucidated. Here, we evaluated the role of long noncoding (lnc)RNA TCONS_00077866 (lnc866) in SA-induced β
cell inflammation. lnc866 was selected for study because lncRNA high-throughput sequencing analysis demonstrated it to have the largest fold-difference in expression of five lncRNAs that were affected by SA treatment. Knockdown of lnc866 by virus-mediated shRNA expression in mice or by Smart Silencer in mouse pancreatic β-TC6 cells significantly inhibited the SA-induced reduction in insulin secretion and β-cell inflammation. According to lncRNA-miRNAs-mRNA coexpression network analysis and luciferase reporter assays, lnc866 directly bound to miR-297b-5p, thereby preventing it from reducing the expression of its target serum amyloid A3 (SAA3). Furthermore, overexpression of miR-297b-5p or inhibition of SAA3 also had marked protective effects against the deleterious effects of SA in β-TC6 cells and mouse islets. In conclusion, lnc866 silencing ameliorates SA-induced β
cell inflammation by targeting the miR-297b-5p/SAA3 axis. lnc866 inhibition may represent a new strategy to protect β-cells against the effects of SA during the development of type 2 diabetes.