MiR-221/222调控肝脏糖脂代谢的作用机制研究

Along with the continuous increase of the prevalence of chronic metabolic disease, disorder of hepatic glucose and lipid metabolism has become an important clinical problem. Mechanisms and regulations of the factors, which play key roles in liver glucose and lipid metabolism, have become new research focus. Our research group is committed to studies regarding the regulatory mechanisms of liver metabolic homeostasis in a long history. We found that miR-221/222 were up-regulated in the liver of metabolic imbalanced mouse models. By use of hepatocyte-specific miR-221/222 knockout mice, we found that miR-221/222 plays a pivotal role in the progress of hepatic steatosis caused by the metabolic disturbances. On this basis, our research group will generate hepatocyte-specific miR-221/222 overexpressed mice and continue to explore the precise functions and regulatory mechanisms of miR-221/222 in liver metabolism metastasis. In addition, our studies aim to clarify the effects and mechanisms of antisence oligonucleotides of miR-221/222 in the reversion of hepatic glucose and lipid metabolism disorder in mice and ultimately provide innovative and more effectively preventive approaches and diagnostic markers as well as therapeutic targets, and provide scientific evidence for preventing and slowing the progression of hepatic metabolic disorder.

随着糖尿病、肥胖、血脂异常等慢性代谢性疾病患病率不断增高, 肝脏糖脂代谢紊乱症候群已成为重要临床问题。调控肝脏糖脂代谢中发挥关键作用的因子及其作用机制已成为新的关注热点。申请者长期致力于肝脏代谢稳态的调控机制研究, 在代谢失衡的小鼠模型肝脏中发现miR-221/222表达上调，进一步利用肝细胞特异性miR-221/222敲除小鼠模型, 发现miR-221/222在代谢失衡所致肝脏脂肪变性进展中发挥重要作用。在此基础上,课题组将建立肝脏miR-221/222过表达和靶基因干扰小鼠模型,深入探索miR-221/222在肝脏糖脂代谢中的精确功能与调控机制。利用miR-221/222反义寡核苷酸干预代谢失衡小鼠阐述其在逆转肝脏糖脂代谢紊乱中的作用及机制, 最终提供新的更有效的肝脏糖脂代谢紊乱的预防途径、诊断标志物与治疗靶点, 为预防和延缓肝脏糖脂代谢紊乱提供科学依据。

本项目利用人与小鼠代谢失衡的肝脏组织发现特异性上调的miRNA:miR-221/222，进一步构建肝细胞特异性敲除miR-221/222小鼠模型，发现在MCDD喂养的小鼠模型中，miR-221/222肝缺失可显著减轻脂质沉积、炎症浸润和肝纤维化。miR-221/222-LKO小鼠经miR-221/222再表达可显著加重肝脏脂肪变性和纤维化。miR-221/222的抑制剂能有效地降低MCDD介导的肝脂肪变性和纤维化。深入地探讨了miR-221/222在肝脏脂代谢和纤维化中的作用。在此基础上,深入分析了miR-221/222在肝脏纤维化中的精确功能与调控机制，发现肝脏miR-221/222通过调控靶基因Timp3的表达，促进NASH的进展。 利用miR-221/222反义寡核苷酸干预肝脏纤维化小鼠并阐述其在逆转肝脏纤维化中的作用及机制, 可以提供新的更有效的肝脏纤维化的诊断标志物与治疗靶点, 为延缓肝脏纤维化提供科学依据。