Table_2_miR-344-5p Modulates Cholesterol-Induced β-Cell Apoptosis and Dysfunction Through Regulating Caveolin-1 Expression.docx

Diabetes is a metabolic disorder induced by the modulation of insulin on glucose metabolism, and the dysfunction and decreased number of islets β-cells are the main causes of T2DM (type 2 diabetes mellitus). Among multiple factors that might participate in T2DM pathogenesis, the critical roles of miRNAs in T2DM and β-cell dysfunction have been reported. Through bioinformatics analyses and literature review, we found that miR-344 might play a role in the occurrence and progression of diabetes in rats. The expression levels of miR-344-5p were dramatically decreased within cholesterol-stimulated and palmitic acid (PA)-induced rats’ islet β-cells. In cholesterol-stimulated and PA-induced diabetic β-cell model, cholesterol-caused and PA-caused suppression on cell viability, increase in intracellular cholesterol level, decrease in GSIS, and increase in lip droplet deposition were dramatically attenuated via the overexpression of miR-344-5p, whereas aggravated via the inhibition of miR-344-5p. miR-344-5p also inhibited cholesterol-induced β-cell death via affecting the apoptotic caspase 3/Bax signaling. Insulin receptor downstream MPAK/ERK signaling was involved in the protection of miR-344-5p against cholesterol-induced pancreatic β-cell dysfunction. Moreover, miR-344-5p directly targeted Cav1; Cav1 silencing could partially reverse the functions of miR-344-5p inhibition upon cholesterol-induced β-cell dysfunction, β-cell apoptosis, the apoptotic caspase 3/Bax signaling, and insulin receptor downstream MPAK/ERK signaling. In conclusion, the miR-344-5p/Cav1 axis modulates cholesterol-induced β-cell apoptosis and dysfunction. The apoptotic caspase 3/Bax signaling and MAPK/ERK signaling might be involved.

糖尿病是一种由胰岛素调控糖代谢异常所引发的代谢紊乱性疾病，胰岛β细胞功能障碍与数量减少是2型糖尿病（type 2 diabetes mellitus，T2DM）的主要致病原因。在参与T2DM发病机制的诸多因素中，微小RNA（microRNAs，miRNAs）在T2DM及胰岛β细胞功能障碍中的关键作用已被广泛报道。通过生物信息学分析与文献调研，我们发现miR-344可能在大鼠糖尿病的发生与进展中发挥调控作用。在胆固醇刺激及棕榈酸（palmitic acid，PA）诱导的大鼠胰岛β细胞中，miR-344-5p的表达水平显著降低。在胆固醇刺激及PA诱导的糖尿病β细胞模型中，过表达miR-344-5p可显著缓解胆固醇与PA所导致的细胞活力抑制、细胞内胆固醇水平升高、葡萄糖刺激胰岛素分泌（glucose-stimulated insulin secretion，GSIS）降低以及脂滴沉积增加；而抑制miR-344-5p则会加剧上述表型变化。miR-344-5p还可通过调控凋亡相关的半胱天冬氨酸蛋白酶3/B细胞淋巴瘤-2相关X蛋白（caspase 3/Bax）信号通路，抑制胆固醇诱导的β细胞死亡。胰岛素受体下游的丝裂原活化蛋白激酶/细胞外调节蛋白激酶（MAPK/ERK）信号通路参与了miR-344-5p对胆固醇诱导的胰岛β细胞功能障碍的保护作用。此外，miR-344-5p可直接靶向小窝蛋白1（Caveolin-1，Cav1）；沉默Cav1可部分逆转抑制miR-344-5p所产生的、针对胆固醇诱导的β细胞功能障碍、β细胞凋亡、caspase 3/Bax信号通路以及胰岛素受体下游MAPK/ERK信号通路的调控效应。综上，miR-344-5p/小窝蛋白1（Cav1）轴可调控胆固醇诱导的β细胞凋亡与功能障碍，该过程可能涉及caspase 3/Bax信号通路与MAPK/ERK信号通路。