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 acid-stimulated lipotoxicity to β cells. 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. 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 significantly restored stearic acid-impaired glucose-stimulated insulin secretion through alleviating endoplasmic reticulum stress. However, stearic acid-induced β cell apoptosis was not obviously recovered. Our findings suggest the involvement of 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.

中文翻译：

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TCONS_00230836沉默通过减轻内质网应激而非凋亡来恢复硬脂酸诱导的β细胞功能障碍

胰腺β细胞长期暴露于高水平的硬脂酸（C18：0）会导致胰岛素分泌受损，从而加速2型糖尿病（T2DM）的发展。最近，发现长的非编码RNA（lncRNA）参与饱和脂肪酸诱导的代谢功能障碍。然而，它们对硬脂酸诱导的β-细胞功能障碍的贡献仍然未知。这项研究评估了lncRNA TCONS_00230836在硬脂酸刺激的β细胞脂毒性中的可能作用。使用高通量RNA测序，筛选出TCONS_00230836在硬脂酸处理的小鼠β-TC6细胞中仅差异表达。构建共表达网络以揭示针对lncRNA TCONS_00230836的潜在mRNA。通过实时PCR在硬脂酸处理过的β-TC6细胞和喂食高硬脂酸饮食（HSD）的小鼠的胰岛中进一步评估了该lncRNA和候选mRNA水平的变化。通过荧光原位杂交检测TCONS_00230836的定位。β-TC6细胞中的内源性lncRNA TCONS_00230836被其Smart Silencer废除。TCONS_00230836富含小鼠胰岛，主要位于细胞质中。在硬脂酸处理过的β-TC6细胞和HSD喂养的小鼠胰岛中，其表达显着增加。减少TCONS_00230836可以通过减轻内质网应激显着恢复硬脂酸受损的葡萄糖刺激的胰岛素分泌。但是，硬脂酸诱导的β细胞凋亡没有明显恢复。我们的发现表明TCONS_00230836参与了硬脂酸诱导的β细胞功能障碍，这为硬脂酸诱导的对β细胞的脂毒性提供了新的见解。抗-lncRNA TCONS_00230836可能是减轻T2DM进程中硬脂酸诱导的β细胞功能障碍的新治疗策略。