IGF2BP3促进肝脏甘油三酯沉积的作用和机制研究

Non-alcoholic fatty liver disease (NAFLD) has become one of the major chronic non-communicable diseases affecting both the physical and mental health of Chinese people. The characteristic of NAFLD is the excessive accumulation of triglycerides in hepatocytes and obesity is the main risk factor, however, its exact mechanisms have not been fully elucidated. Previously, by using the expression profile chip, we found that the expression of RNA-binding protein - IGF2BP3 was significantly up-regulated in the liver tissue of patients with NAFLD. In addition, the abnormally high expression of IGF2BP3 was also observed in liver tissues of obese mice. Furthermore, overexpression of IGF2BP3 in mouse primary hepatocytes increased the intracellular triglyceride content, and significantly up-regulated the expression of nuclear receptor LXR and its downstream lipid synthesis-related genes. Thus, these original data suggest that IGF2BP3 may promote the synthesis and excessive accumulation of triglycerides by inducing the expression of LXR. In summary, based on the above findings, our project will further reveal the role and mechanism of IGF2BP3 in regulating triglyceride metabolism and promoting liver lipid deposition. The interpretation of this problem will help us to deepen the understanding of the pathophysiological mechanism of NAFLD, and provide new clues and scientific basis for finding the intervention targets of NAFLD and related metabolic diseases.

非酒精性脂肪肝病(NAFLD)已成为影响国人身心健康的重大慢性非传染性疾病之一。NAFLD的实质是肝细胞内甘油三酯的过量积聚，肥胖是其主要危险因素，但机制尚未完全阐明。课题组前期工作中，利用表达谱芯片，发现NAFLD患者肝脏组织中RNA结合蛋白-IGF2BP3的表达显著上调。此外，在肥胖小鼠的肝脏组织中，IGF2BP3也呈现异常高表达。进一步，在小鼠原代肝细胞上过表达IGF2BP3后，细胞内甘油三酯含量增加，核受体LXR及其下游脂质合成相关基因的表达显著上调。由此提示，IGF2BP3可能通过促进LXR的表达，促进甘油三酯的合成和过量堆积。综上所述，本项目将在上述发现的基础上，进一步揭示IGF2BP3调控甘油三酯代谢、促进肝脏脂质沉积的作用及机制。这一问题的阐释，有助于加深对NAFLD病理生理机制的认识和理解，并为寻找NAFLD及相关代谢性疾病的干预靶点提供新的线索和科学依据。

项目的背景：非酒精性脂肪性肝病(Nonalcoholic fatty liver disease, NAFLD)已经成为我国主要慢性肝病，和肥胖、胰岛素抵抗、2型糖尿病等糖脂代谢紊乱密切相关。肝脏甘油三酯沉积是NAFLD的特征性病理表现，可进一步引起肝脏炎症，导致非酒精性脂肪性肝炎（NASH）。.主要研究内容：本项目主要开展了两方面研究，第一部分以mRNA结合蛋白IGF2BP家族蛋白(IGF2BP1, IGF2BP2, IGF2BP3)为切入点，第二部分以miR-185-5p为切入点，研究它们在肝脏糖脂代谢和相关代谢性疾病中的作用及机制。在第一部分中，课题组通过常用的NAFLD/NASH动物模型，发现IGF2BP2表达在NAFLD和NASH小鼠显著升高，进一步借助腺病毒和腺相关病毒介导的肝脏特异性高表达和干扰表达等手段，发现IGF2BP2具有促进肝脏脂质沉积、炎症和纤维化的作用。在第二部分中，课题组采用microRNA高通量测序鉴定差异表达的miRNAs，采用高脂饮食诱导的肥胖C57BL/6小鼠和糖尿病遗传性小鼠db/db小鼠，研究miR-185-5p对肝脏糖异生的调节作用和分子机制。.重要结果和关键数据：通过两部分的研究，课题组揭示了IGF2BPs家族蛋白在NAFLD-NASH进程中的表达规律，发现并阐明了IGF2BP2在NAFLD-NASH中的作用和机制；筛选了调节肝脏糖脂代谢的miRNA家族，揭示了miR-185-5p通过调节糖异生关键酶G6Pase表达，抑制肝脏糖异生和改善2型糖尿病的作用。.科学意义：上述研究不仅进一步揭示了NAFLD和肝脏糖脂代谢紊乱的发病机制，也为相关疾病的治疗提供了新型干预靶点。