Abstract
BackgroundChronic 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.MethodUsing 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.ResultsTCONS_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.ConclusionOur 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.
Highlights
Chronic exposure to elevated saturated fatty acids (SFAs) of pancreatic β cells is a key trigger of impaired insulin secretion, which is one of the most important characteristics of type 2 diabetes mellitus (T2DM)
Using RNA-sequencing and Quantitative real-time PCR (qRT-PCR), we showed for the first time that the long noncoding RNAs (lncRNAs) TCONS_00230836 was differentially expressed exclusively in stearic acid-treated β-TC6 cells, compared with both palmitic acid-treated cellsand control cells
The results obtained by high-throughput RNAsequencing demonstrated that the lncRNA TCONS_ 00230836, an intergenic lncRNA located at 65803111 to 65809116 of chromosome 10, was markedly elevated with a 1.328 log2 fold change (P value: 5.062E-07) in βTC6 cells exposed to stearic acid and a 0.270 log2 fold change (P value: 0.327) in the palmitic acid-treated cells, compared with the level in control cells (Fig. 1a)
Summary
Chronic exposure to elevated saturated fatty acids (SFAs) of pancreatic β cells is a key trigger of impaired insulin secretion, which is one of the most important characteristics of type 2 diabetes mellitus (T2DM). Endoplasmic reticulum (ER) stress [5, 9] and apoptosis [8, 10] are accepted as major contributors to stearic acid-induced β cell dysfunction, the molecular mechanisms involved in this remain largely unclear. 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). Long noncoding RNAs (lncRNAs) were found to participate in saturated fatty acid-induced metabolism dysfunction. 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
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