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首页> 外文期刊>RSC Advances >Ezetimibe alleviates non-alcoholic fatty liver disease through the miR-16 inhibiting mTOR/p70S6K1 pathway
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Ezetimibe alleviates non-alcoholic fatty liver disease through the miR-16 inhibiting mTOR/p70S6K1 pathway

机译：依泽替米贝通过miR-16抑制mTOR / p70S6K1途径缓解非酒精性脂肪肝疾病

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Emerging studies have indicated the role of ezetimibe, miR-16 and mTOR signaling in non-alcoholic fatty liver disease (NAFLD). However, few studies have demonstrated their correlation and regulation functions in NAFLD. Therefore, the protective effect of ezetimibe in NAFLD and the potential mechanisms were explored in the current study. A NAFLD in vivo rat model was established. In addition, a rat hepatocyte cell line, BRL3A, was treated with 1 mM free fatty acids (FFA) to induce NAFLD in vitro. Hepatic triglyceride and lipid metabolism genes (ACC, Fas) and serum biochemical parameters (cholesterol, ALT) were measured. miR-16 and mTOR/p70S6K1 pathway protein expression in both rat livers and cultured cells was also assessed. The direct targeting relationship between miR-16 and mTOR was determined by the dual luciferase reporter gene assay. BRL3A cells were transfected with an miR-16 mimic for in vitro functional studies, and HFD-fed rats were tail vein injected with miR-16 inhibitor and in vivo experimental validation was carried out. NAFLD models both in vivo and in vitro were established successfully. The expression of hepatic triglyceride and lipid metabolism genes was increased and serum biochemical parameters, miR-16 and mTOR/p70S6K1 pathway proteins, were unusually expressed in NAFLD rats and BRL3A cells. Ezetimibe was found to alleviate abnormal expression of these molecules. Through the dual luciferase reporter gene assay, we found that mTOR was a target gene of miR-16. In addition, miR-16 over-expression could reverse the up-regulation of lipid metabolism genes in BRL3A cells, while this effect could be attenuated by pcDNA-mTOR. Ezetimibe significantly reduced the expression of ACC and Fas. After rapamycin treatment, the action of ezetimibe in regulating Fas and AAC was not reversed; however, rapamycin further reduced the expression of ACC and Fas. Silencing miR-16 reversed the protections given by ezetimibe in HFD rats, which showed up-regulated hepatic triglyceride, lipid metabolism genes, serum biochemical parameters and mTOR/p70S6K1 pathway proteins. Ezetimibe alleviated NAFLD induced by a HFD, at least partly, through inhibition of the mTOR/p70S6K1 pathway by miR-16 and affecting the regulation of lipid metabolism, which provides a therapeutic method for NAFLD.
机译：新兴研究表明，依泽替米贝，miR-16和mTOR信号在非酒精性脂肪肝疾病（NAFLD）中的作用。但是，很少有研究证明它们在NAFLD中具有相关性和调节功能。因此，本研究探讨了依泽替米贝对NAFLD的保护作用及其潜在机制。建立了NAFLD 体内大鼠模型。此外，用1 mM游离脂肪酸（FFA）处理大鼠肝细胞BRL3A，以在体外诱导NAFLD。测量了肝甘油三酸酯和脂质代谢基因（ACC，Fas）以及血清生化参数（胆固醇，ALT）。还评估了大鼠肝脏和培养细胞中的miR-16和mTOR / p70S6K1途径蛋白表达。 miR-16和mTOR之间的直接靶向关系是通过双重萤光素酶报告基因测定的。用miR-16模拟物转染BRL3A细胞以进行体外功能研究，并向喂食HFD的大鼠尾静脉注射miR-16抑制剂，并通过体内实验验证执行。成功建立了体内和体外的NAFLD模型。肝甘油三酸酯和脂质代谢基因的表达增加，并且血清生化参数，miR-16和mTOR / p70S6K1通路蛋白在NAFLD大鼠和BRL3A细胞中异常表达。发现依泽替米贝减轻了这些分子的异常表达。通过双重荧光素酶报告基因检测，我们发现mTOR是miR-16的靶基因。此外，miR-16的过表达可以逆转BRL3A细胞中脂质代谢基因的上调，而pcDNA-mTOR可以减弱这种作用。依泽替米贝显着降低ACC和Fas的表达。雷帕霉素治疗后，依泽替米贝在调节Fas和AAC中的作用没有被逆转。然而，雷帕霉素进一步降低了ACC和Fas的表达。沉默miR-16逆转了依泽替米贝对HFD大鼠的保护作用，后者显示肝甘油三酸酯，脂质代谢基因，血清生化参数和mTOR / p70S6K1途径蛋白上调。依泽替米贝至少部分地通过miR-16抑制mTOR / p70S6K1途径并影响脂质代谢的调节来缓解HFD诱导的NAFLD，这为NAFLD提供了一种治疗方法。

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