Department of Biochemistry, College of Medicine, Dongguk University, 123 Dongdae-ro, Gyeongju 38066, Korea.
Channelopathy Research Center, College of Medicine, Dongguk University, 32 Dongguk-ro, Ilsan Dong-gu, Goyang 10326, Korea.
Int J Mol Sci. 2022 Mar 10;23(6):2979. doi: 10.3390/ijms23062979.
Excessive saturated fatty acids (SFA) uptake is known to be a primary cause of obesity, a widely acknowledged risk factor of insulin resistance and type 2 diabetes. Although specific microRNAs (miRNAs) targeting insulin signaling intermediates are dysregulated by SFA, their effects on insulin signaling and sensitivity are largely unknown. Here, we investigated the role of SFA-induced miR-183-5p in the regulation of proximal insulin signaling molecules and the development of hepatic insulin resistance. HepG2 hepatocytes treated with palmitate and the livers of high-fat diet (HFD)-fed mice exhibited impaired insulin signaling resulting from dramatic reductions in the protein expressions of insulin receptor (INSR) and insulin receptor substrate-1 (IRS-1). Differential expression analysis showed the level of miR-183-5p, which tentatively targets the 3'UTR of , was significantly elevated in palmitate-treated HepG2 hepatocytes and the livers of HFD-fed mice. Dual-luciferase analysis showed miR-183-5p bound directly to the 3'UTR of and reduced IRS-1 expression at the post-transcriptional stage. Moreover, transfection of HepG2 hepatocytes with miR-183-5p mimic significantly inhibited IRS-1 expression and hindered insulin signaling, consequently inhibiting insulin-stimulated glycogen synthesis. Collectively, this study reveals a novel mechanism whereby miR-183-5p induction by SFA impairs insulin signaling and suggests miR-183-5p plays a crucial role in the pathogenesis of hepatic insulin resistance in the background of obesity.
已知过多的饱和脂肪酸（SFA）摄取是肥胖的主要原因，而肥胖是胰岛素抵抗和 2 型糖尿病的公认危险因素。尽管特定的针对胰岛素信号转导中间物的 microRNAs（miRNAs）被 SFA 失调，但它们对胰岛素信号转导和敏感性的影响在很大程度上尚不清楚。在这里，我们研究了 SFA 诱导的 miR-183-5p 在调节胰岛素信号转导近端分子和肝胰岛素抵抗发展中的作用。用棕榈酸处理的 HepG2 肝细胞和高脂肪饮食（HFD）喂养的小鼠的肝脏表现出胰岛素信号受损，这是由于胰岛素受体（INSR）和胰岛素受体底物-1（IRS-1）的蛋白表达显着降低所致。差异表达分析显示，miR-183-5p 的水平明显升高，miR-183-5p 暂定靶向 3'UTR，在棕榈酸处理的 HepG2 肝细胞和 HFD 喂养的小鼠的肝脏中显着升高。双荧光素酶分析显示，miR-183-5p 直接与 3'UTR 结合，并在转录后阶段降低 IRS-1 表达。此外，用 miR-183-5p 模拟物转染 HepG2 肝细胞可显着抑制 IRS-1 表达并阻碍胰岛素信号转导，从而抑制胰岛素刺激的糖原合成。总之，这项研究揭示了 SFA 诱导的 miR-183-5p 损害胰岛素信号转导的新机制，并表明 miR-183-5p 在肥胖背景下肝胰岛素抵抗的发病机制中起关键作用。
