Alterations in microRNA expression contribute to fatty acid-induced pancreatic beta-cell dysfunction.
Alterations in microRNA expression contribute to fatty acid-induced pancreatic beta-cell dysfunction.
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作者：
Lovis P;Roggli E;Laybutt DR;Gattesco S;Yang JY;Widmann C;Abderrahmani A;Regazzi R
内脏肥胖和血浆游离脂肪酸升高是2型糖尿病的易感因素。长期暴露于这些脂质对胰腺β细胞有害，导致胰岛素含量降低、胰岛素分泌缺陷和细胞凋亡。我们研究了参与这种现象的microRNAs（miRNAs），一类通过序列特异性抑制mRNA翻译来调节基因表达的非编码RNA。研究设计和方法-我们分析了暴露于棕榈酸3天的胰岛素分泌细胞系或胰岛以及糖尿病db/db小鼠胰岛中的miRNA表达。我们研究了触发miRNA表达变化的信号通路，并确定了棕榈酸酯对胰岛素分泌和细胞凋亡的影响。β-细胞系MIN 6 B1和胰岛长期暴露于棕榈酸酯导致miR 34 a和miR 146的时间和剂量依赖性增加。在糖尿病db/db小鼠的胰岛中也观察到这些miRNA水平升高。miR 34 a升高与p53的活化有关，并导致对细胞凋亡的敏感性和营养诱导的分泌受损。后一种效应与抑制囊泡相关膜蛋白2的表达有关，囊泡相关膜蛋白2是β细胞胞吐的关键参与者。较高的miR 146水平不影响释放胰岛素的能力，但有助于增加细胞凋亡。用阻断miR 34 a或miR 146活性的寡核苷酸处理部分保护棕榈酸酯处理的细胞免于凋亡，但不足以恢复正常分泌。结论-我们的发现表明，棕榈酸对β细胞的有害作用至少有一部分是由特定miRNA水平的改变引起的。
OBJECTIVE—Visceral obesity and elevated plasma free fatty acids are predisposing factors for type 2 diabetes. Chronic exposure to these lipids is detrimental for pancreatic β-cells, resulting in reduced insulin content, defective insulin secretion, and apoptosis. We investigated the involvement in this phenomenon of microRNAs (miRNAs), a class of noncoding RNAs regulating gene expression by sequence-specific inhibition of mRNA translation. RESEARCH DESIGN AND METHODS—We analyzed miRNA expression in insulin-secreting cell lines or pancreatic islets exposed to palmitate for 3 days and in islets from diabetic db/db mice. We studied the signaling pathways triggering the changes in miRNA expression and determined the impact of the miRNAs affected by palmitate on insulin secretion and apoptosis. RESULTS—Prolonged exposure of the β-cell line MIN6B1 and pancreatic islets to palmitate causes a time- and dose-dependent increase of miR34a and miR146. Elevated levels of these miRNAs are also observed in islets of diabetic db/db mice. miR34a rise is linked to activation of p53 and results in sensitization to apoptosis and impaired nutrient-induced secretion. The latter effect is associated with inhibition of the expression of vesicle-associated membrane protein 2, a key player in β-cell exocytosis. Higher miR146 levels do not affect the capacity to release insulin but contribute to increased apoptosis. Treatment with oligonucleotides that block miR34a or miR146 activity partially protects palmitate-treated cells from apoptosis but is insufficient to restore normal secretion. CONCLUSIONS—Our findings suggest that at least part of the detrimental effects of palmitate on β-cells is caused by alterations in the level of specific miRNAs.
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