TCONS_00230836 silencing restores stearic acid-induced β-cell dysfunction through alleviating endoplasmic reticulum stress via a PERK/eIF2α-dependent pathway rather than apoptosis [post]

Rui Guo, Yunjin Zhang, Yue Yu, Shenghan Su, Qingrui Zhao, Xia Chu, Huimin Lu, Changhao Sun
2020 unpublished
Background: Chronic exposure of pancreatic β cells to high levels of stearic acid (C18:0) leads to impaired insulin secretion, which accelerates the progression of type 2 diabetes mellitus (T2DM). Recently, long noncoding RNAs (lncRNAs) were found to participate in saturated fatty acid-induced metabolism dysfunction. However, their contribution to stearic acid-induced β-cell dysfunction remains largely unknown. This study evaluated the possible role of the lncRNA TCONS_00230836 in stearic
more » ... 36 in stearic acid-stimulated lipotoxicity to β cells. Method: Using high-throughput RNA-sequencing, TCONS_00230836 was screened out as being exclusively differentially expressed in stearic acid-treated mouse β-TC6 cells. Co-expression network was constructed to reveal the potential mRNAs targeted for lncRNA TCONS_00230836. Changes in this lncRNA's and candidate mRNAs'levels were further assessed by real-time PCR in stearic acid-treated β-TC6 cells and islets of mice fed a high-stearic-acid diet (HSD). The localization of TCONS_00230836 was detected by fluorescent in situ hybridization. The endogenous lncRNA TCONS_00230836 in β-TC6 cells was abrogated by its Smart Silencer. Results: The lncRNA TCONS_00230836 was enriched in mouse islets and mainly localized in the cytoplasm. Its expression was significantly increased in stearic acid-treated β-TC6 cells and HSD-fed mouse islets. Knockdown of TCONS_00230836 apparently restored stearic acid-impaired GSIS through alleviating endoplasmic reticulum stress via a PERK/eIF2α-dependent pathway. However, stearic acid-induced β-cell apoptosis was not obviously recovered. Conclusion: Our findings suggest the involvement of the lncRNA TCONS_00230836 in stearic acid-induced β-cell dysfunction, which provides novel insight into stearic acid-induced lipotoxicity to β cells. Anti-lncRNA TCONS_00230836 might be a new therapeutic strategy for alleviating stearic acid-induced β-cell dysfunction in the progression of T2DM.
doi:10.21203/rs.3.rs-71491/v1 fatcat:fjf53dfqivg3fpbezjnszifdge