miR-361调控肝脏糖脂代谢的作用及机制研究

Metabolic disorders, including type 2 diabetes (T2DM) and non-alcoholic fatty liver disease (NAFLD), have become main public health problems in China. MicroRNAs play a critical role in the regulation of glucose and lipid homeostasis. Our previous work demonstrated that miR-361 was significantly upregulated in the livers of obese mice and humans. Notably, mice overexpressing miR-361 in the liver exhibited hyperglycemia, hepatosteatosis and impaired insulin sensitivity. At the molecular level, miR-361 inhibits the expression of Sirt1, a key regulator involved in glucose and lipid homeostasis. Therefore, we proposed that miR-361 could promote metabolic disorders through inhibition of Sirt1 expression. Based on these findings, we will further focus on: 1) the role of miR-361 in the regulation of hepatic glucose and lipid metabolism; 2) the molecular mechanism of miR-361 implicating in metabolic disorders. Our study will lead to a better understanding of the pathogenesis of hepatic glucose and lipid metabolism disorders, and also provide a potential target for related diseases.

2型糖尿病（T2DM）、非酒精性脂肪肝病（NAFLD）等代谢性疾病已严重危害人类健康。MicroRNA在维持肝脏乃至全身糖脂代谢稳态平衡中发挥重要的作用。本课题前期研究发现：肥胖小鼠和患者肝脏组织中，miR-361的表达显著上调。利用腺病毒介导的肝脏特异性miR-361过表达后，小鼠出现胰岛素敏感性受损、血糖升高、肝脏甘油三酯沉积增加，同时肝脏糖脂代谢关键分子Sirt1的表达受到明显抑制，提示肥胖时，miR-361可能通过靶向抑制Sirt1的表达，促进肝脏糖脂代谢紊乱的发生。本项目将在这些重要发现的基础上，运用多种现代分子生物学方法，开展以下研究：1）明确miR-361对肝脏糖脂代谢的调控作用；2）阐明miR-361调控肝脏糖脂代谢的分子机制。本课题的开展，将不仅有助于揭示肝脏糖脂代谢紊乱的发病机制，也为2型糖尿病、非酒精性脂肪性肝病等糖脂代谢紊乱性疾病的预防和治疗提供新的靶点。

2型糖尿病（T2DM）、非酒精性脂肪肝病（NAFLD）等代谢性疾病已严重危害人类健康, 然而其发病机制目前尚未完全阐明。近年来，诸多研究显示MicroRNA在维持肝脏乃至全身糖脂代谢稳态平衡中发挥重要的作用。本研究旨在探讨miR-361在肝脏糖脂代谢紊乱发生中的病理生理学作用及机制。本课题研究发现：1）肥胖小鼠和患者肝脏组织中，miR-361的表达显著上调；2）利用腺病毒介导的肝脏特异性miR-361过表达后，小鼠出现胰岛素敏感性受损、血糖升高、肝脏甘油三酯沉积增加；然而，利用反义锁核酸（LNA）技术抑制肥胖小鼠体内miR-361的表达，则改善胰岛素抵抗、减少肝脏甘油三酯沉积；3）进一步明确miR-361调控肝脏糖脂代谢的分子机制，发现miR-361通过靶向抑制Sirt1的表达，促进胰岛素抵抗、血糖升高及肝脏甘油三酯沉积。本课题的开展，不仅揭示了肝脏糖脂代谢紊乱新的发病机制，也为2型糖尿病、非酒精性脂肪性肝病等糖脂代谢紊乱性疾病的预防和治疗提供新的靶点。