Agency for Science Technology and Research, Singapore.
Hepatology. 2014 Aug;60(2):554-64. doi: 10.1002/hep.27153. Epub 2014 May 19.
The incidence of nonalcoholic fatty liver disease (NAFLD) and hyperlipidemia, with their associated risks of endstage liver and cardiovascular diseases, is increasing rapidly due to the prevalence of obesity. Although the mechanisms of NAFLD have been studied extensively, the underlying pathogenesis and the role of microRNAs in this process remain relatively unclear. MicroRNA (miRNA)-dependent posttranscriptional gene silencing is now recognized as a key element of lipid metabolism. Here we report that the expression of microRNA-24 (miR-24) is significantly increased in the livers of high-fat diet-treated mice and in isolated human hepatocytes incubated with fatty acid. Knockdown of miR-24 in those mice caused impaired hepatic lipid accumulation and reduced plasma triglycerides. Bioinformatic and in vitro and in vivo studies led us to identify insulin-induced gene 1 (Insig1), an inhibitor of lipogenesis, as a novel target of miR-24. Inhibition of endogenous miR-24 expression by way of miR-24 inhibitors led to up-regulation of Insig1, and subsequently decreased hepatic lipid accumulation. It is well established that liver-specific deletion of Insig1 leads to higher hepatic and plasma triglyceride levels by inhibiting the processing of sterol regulatory element-binding proteins (SREBPs), transcription factors that activate lipid synthesis. As expected, miR-24 knockdown prevented SREBP processing, and subsequent expression of lipogenic genes. In contrast, the opposite result was observed with overexpression of miR-24, which enhanced SREBP processing. Thus, our study defines a potentially critical role for deregulated expression of miR-24 in the development of fatty liver by way of targeting of Insig1.
Our findings show a novel mechanism by which miR-24 promotes hepatic lipid accumulation and hyperlipidemia by repressing Insig1, and suggest the use of miR-24 inhibitor as a potential therapeutic agent for NAFLD and/or atherosclerosis.
由于肥胖症的流行，非酒精性脂肪性肝病 (NAFLD) 和高脂血症的发病率及其相关的终末期肝病和心血管疾病风险迅速增加。尽管已经广泛研究了 NAFLD 的机制，但该疾病的潜在发病机制和 microRNA 在该过程中的作用仍相对不清楚。microRNA (miRNA)-依赖性转录后基因沉默现在被认为是脂质代谢的关键因素。在这里，我们报告说，高脂肪饮食处理的小鼠肝脏中和与脂肪酸孵育的分离的人肝细胞中，microRNA-24 (miR-24) 的表达显著增加。在这些小鼠中敲低 miR-24 导致肝脂质积累受损和血浆甘油三酯降低。生物信息学以及体外和体内研究使我们鉴定出胰岛素诱导基因 1 (Insig1)，一种脂肪生成抑制剂，为 miR-24 的一个新靶标。通过 miR-24 抑制剂抑制内源性 miR-24 表达导致 Insig1 上调，随后肝脂质积累减少。众所周知，通过抑制固醇调节元件结合蛋白 (SREBP) 的加工，肝特异性缺失 Insig1 会导致肝和血浆甘油三酯水平升高，SREBP 是激活脂质合成的转录因子。正如预期的那样，miR-24 敲低阻止了 SREBP 的加工，随后抑制了脂肪生成基因的表达。相反，过表达 miR-24 则观察到相反的结果，这增强了 SREBP 的加工。因此，我们的研究通过靶向 Insig1 定义了 miR-24 表达失调在脂肪性肝病发展中的潜在关键作用。
我们的研究结果表明，miR-24 通过抑制 Insig1 促进肝脂质积累和高脂血症的一种新机制，并表明使用 miR-24 抑制剂作为治疗非酒精性脂肪性肝病和/或动脉粥样硬化的潜在治疗剂。
