SDF2L1调控肝脏脂质沉积和胰岛素抵抗的机制研究

Abnormal regulation of hepatic glucose and lipid metabolism often leads to lipid accumulation and insulin resistance, which is an important pathogenic factor for metabolic syndrome, including type 2 diabetes and fatty liver. Recent studies showed that stromal cell-derived factor 2-like 1 (SDF2L1) is tightly associated with the pathophysiology of diabetes. However, the metabolic function of SDF2L1 and its downstream signals remain unkown. Our preliminary results demonstrated that hepatic SDF2L1 expression was down-regulated in diabetic and obese mice, while the presence of insulin could increase hepactic expression of SDF2L1. Overexpression of SDF2L1 in primary hepatocytes suppressed the expression of lipogenic genes，including SREBP-1c, FAS, ACC, thereby reducing cellular triacylglycerol concentration. These results suggest that SDF2L1 plays a critical role in regulation of hepatic lipid metabolism and insulin sensitivity. In this project, we will use adenovirus expression system to investigate the effect of hepatic SDF2L1 on fatty liver disease and diabetes, and explore the underlying mechanisms. Our study will provide potential strategies for clinical diagnosis and treatment of fatty liver disease and diabetes.

肝脏糖脂代谢异常常导致肝脏脂质沉积和胰岛素抵抗，是糖尿病、脂肪肝等代谢性疾病关键的致病因素，探索其调控机制，有利于阐明代谢性疾病的发病机理。研究表明基质细胞衍生因子SDF2L1与代谢性疾病密切相关，但其如何调控肝脏糖脂代谢和胰岛素抵抗目前尚不清楚。我们的预实验发现，肥胖和2型糖尿病小鼠肝脏中SDF2L1表达下降，而腹腔注射胰岛素则可上调SDF2L1在肝脏中的表达。在肝脏原代细胞中过表达SDF2L1可使甘油三酯含量显著降低，同时伴随有SREBP-1c等脂肪合成基因的表达下调。这些结果提示SDF2L1可能参与调控肝脏脂代谢和胰岛素敏感性。本项目拟利用腺病毒系统上调或敲低SDF2L1表达的方法，通过分子、细胞和动物水平的研究，揭示SDF2L1调控肝脏脂质沉积和胰岛素抵抗的分子机制。本研究不仅能加深我们对肝脏糖脂代谢调控机制的了解，还可为临床防治脂肪肝和糖尿病提供新的理论依据。

非酒精性脂肪肝病(Non-alcoholic fatty liver disease, NAFLD)是世界范围的公共卫生问题。菌群-肠-肝轴在NAFLD发病中发挥着重要作用，寻找其干预策略可能为治疗脂肪肝等代谢性疾病提供新思路。香菇多糖（Lentinan），提取自香菇的1-3, 1-6 β-葡聚糖是重要的免疫调节剂，但其是否能改善饮食诱导的NAFLD目前尚未见报道。本课题发现，膳食补充Lentinan可以改善高脂饮食小鼠的肠道菌群紊乱、降低血清LPS含量和增加肠粘膜屏障完整性。在肝脏中，通过膳食补充Lentinan可以改善高脂饮食小鼠肝脏脂质沉积、抑制肝脏炎症和NFκB-PTP1B-Akt-GSK3β信号通路。同时，相关性分析发现，肝脏相关指标的改变与肠道菌群变化具有明显的相关性。这些结果提示，Lentinan可能通过调节菌群-肠-肝轴来改善NAFLD。另外，本课题还发现，SDF2L1在对乙酰氨基酚（Acetaminophen，APAP）诱导的小鼠肝脏损伤模型中表达量下调，肝脏特异性过表达SDF2L1可以改善小鼠肝脏损伤，SDF2L1对内质网应激的调控在此过程中发挥着重要作用。本研究为脂肪肝和肝脏损伤等疾病的防治提供了新的思路。