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首页> 外文期刊>Biochimica et Biophysica Acta. Gene Regulatory Mechanisms >MiR-107 orchestrates ER stress induction and lipid accumulation by post-transcriptional regulation of fatty acid synthase in hepatocytes
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MiR-107 orchestrates ER stress induction and lipid accumulation by post-transcriptional regulation of fatty acid synthase in hepatocytes

机译：MiR-107通过转录后调节肝细胞中的脂肪酸合酶来协调内质网应激诱导和脂质蓄积

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摘要

MicroRNAs, a class of small non-coding RNAs, are believed to regulate several biological pathways and processes and are implicated in several diseases. They mostly regulate the levels of their target genes at the post transcriptional stage by primarily binding to the 3' UTR. Elevated hepatic levels of miR-107 are a consistent feature associated with several obese and diabetic models. Here, we show that miR-107 post-transcriptionally regulates fatty acid synthase (FASN) by binding to its 3' UTR and reduces its protein levels and the 3'UTR luciferase reporter activity, which are blunted by the miR-107 inhibitor and mutation in the miR-107 binding site in the 3' UTR. Knock-down of endogenous miR-107 levels increased FASN levels in a dose-dependent manner. Overexpression of miR-107 led to significant accumulation of malonyl CoA, accompanied by ER stress induction. All these events were prevented in the presence of the miR-107 inhibitor. While overexpression of FASN could attenuate miR-107 mediated ER stress markers' induction; the ER stress inhibitor, 4-phenyl-butyric acid did not rescue miR-107 induced FASN inhibition. This was followed by increased triglyceride formation and lipid accumulation in the presence of miR-107. These indicate that miR-107 inhibits FASN levels by binding to its 3' UTR and this interaction promotes ER stress induction and malonyl CoA and lipid accumulation in HepG2 cells and primary hepatocytes. Our results suggest that increased levels of miR-107 are critical in promoting lipid accumulation in hepatocytes and this might form the basis of diverse etiologies encountered in a fatty liver.
机译：MicroRNA是一类小的非编码RNA，被认为可调节多种生物学途径和过程，并涉及多种疾病。它们主要通过主要结合3'UTR来调节转录后阶段靶基因的水平。肝脏miR-107水平升高是与几种肥胖和糖尿病模型相关的一致特征。在这里，我们显示miR-107通过结合其3'UTR转录后调节脂肪酸合酶（FASN）并降低其蛋白质水平和3'UTR荧光素酶报道分子的活性，这被miR-107抑制剂和突变所削弱在3'UTR的miR-107结合位点中。内源性miR-107水平的降低以剂量依赖的方式增加了FASN水平。 miR-107的过表达导致丙二酰辅酶A大量积累，并伴有内质网应激诱导。在miR-107抑制剂存在下，所有这些事件均得到预防。 FASN的过表达可以减弱miR-107介导的ER应激标志物的诱导。 ER应激抑制剂4-苯基丁酸不能挽救miR-107诱导的FASN抑制作用。在miR-107存在的情况下，甘油三酸酯形成和脂质蓄积增加。这些表明，miR-107通过与其3'UTR结合来抑制FASN的水平，这种相互作用促进了ER应激的诱导以及丙二酰辅酶A和HepG2细胞和原代肝细胞中脂质的蓄积。我们的研究结果表明，miR-107水平的升高对于促进肝细胞脂质积累至关重要，这可能构成脂肪肝中多种病因的基础。

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