Induction of miR-96 by Dietary Saturated Fatty Acids Exacerbates Hepatic Insulin Resistance through the Suppression of INSR and IRS-1

Obesity is defined as the excessive accumulation of body fat that ultimately leads to chronic metabolic diseases. Diets rich in saturated fatty acids (SFA) exacerbate obesity and hepatic steatosis, which increase the risk of hepatic insulin resistance and type 2 diabetes (T2DM). Although microRNAs (miRNAs) play an important role in a range of biological processes, the implications of SFA-induced miRNAs in metabolic dysregulation, particularly in the pathogenesis of hepatic insulin resistance, are not well understood. This study investigated the implications of miR-96, which is induced strongly by SFA, in the development of hepatic insulin resistance. The liver of HFD mice and the palmitate-treated hepatocytes exhibited an impairment of insulin signaling due to the significant decrease in INSR and IRS-1 expression. According to expression profiling and qRT-PCR analysis of the miRNAs, the expression level of miR-96 was higher in hepatocytes treated with palmitate. Moreover, miR-96 was also upregulated in the liver of HFD mice. Interestingly, miR-96 targeted the 3’UTRs of INSR and IRS-1 directly, and repressed the expression of INSR and IRS-1 at the post-transcriptional level. Accordingly, the overexpression of miR-96 was found to cause a significant decrease in INSR and IRS-1 expression, thereby leading to an impairment of insulin signaling and glycogen synthesis in hepatocytes. These results reveal a novel mechanism whereby miR-96 promotes the pathogenesis of hepatic insulin resistance resulted from SFA or obesity.

肥胖被定义为体内脂肪过度蓄积，最终可诱发慢性代谢性疾病。富含饱和脂肪酸（SFA）的膳食会加重肥胖与肝脂肪变性，进而增加肝脏胰岛素抵抗与2型糖尿病（T2DM）的发病风险。尽管微小RNA（miRNAs）在诸多生物学过程中发挥重要调控作用，但饱和脂肪酸诱导的miRNAs在代谢紊乱，尤其是肝脏胰岛素抵抗的发病机制中的作用仍未被充分阐明。本研究探究了受饱和脂肪酸强力诱导的miR-96在肝脏胰岛素抵抗发生发展中的作用。实验结果显示，高脂饮食（HFD）小鼠的肝脏及经棕榈酸处理的肝细胞均出现胰岛素信号通路受损，具体表现为胰岛素受体（INSR）与胰岛素受体底物1（IRS-1）的表达水平显著下调。通过miRNAs表达谱分析与实时定量聚合酶链反应（qRT-PCR）检测发现，经棕榈酸处理的肝细胞中miR-96的表达水平显著升高；此外，高脂饮食小鼠的肝脏组织内miR-96的表达同样呈现上调趋势。值得注意的是，miR-96可直接靶向结合INSR与IRS-1的3'非翻译区（3’UTRs），并在转录后水平抑制二者的基因表达。进一步实验证实，过表达miR-96可显著降低INSR与IRS-1的表达水平，进而导致肝细胞内胰岛素信号通路受损及糖原合成能力下降。本研究结果揭示了一条全新的分子机制：miR-96可通过该通路促进饱和脂肪酸或肥胖诱导的肝脏胰岛素抵抗的发病过程。