TGFβ协同FFA介导肝细胞释放的胞外囊泡在NASH及系统胰岛素抵抗中的作用

Inflammation due to hepatic lipid metabolic disorder is the major cause of insulin resistance, nonalcoholic steatohepatitis, type 2 diabetes and HCC. The mechanism of the steatotic hepatocytes mediated local and distant metabolic inflammation is still unknown. Extracellular vesicles(EVs) are emerging as critical modulators of intercellular communication, which transmit signaling biomolecules between cells, alter recipient cell phenotypes and induce local and distant inflammation. Our previous study confirmed that TGFβ signaling in hepatocytes promotes steatohepatitis and systemic insulin resistance, but the mechanism is unknown. In this study, we focus on the synergistic role of TGFβ signaling and free fatty acid on hepatocytes releasing extracellular vesicles in nonalcoholic steatohepatitis. We will examine the molecular characteristics of EVs released from hepatocytes in response to TGFβ1 and free fatty acids; define the role of these hepatocyte-derived EVs in the phenotypic modification of hepatocytes, Kupffer cells, stellate cells, skeletal muscle cells, pancreatic cells and endothelial cells. We will also explore the role of these hepatocyte-derived EVs in nonalcoholic steatohepatitis and systemic insulin resistance by delivering hepatocyte-derived EVs in animal models of NASH to determine their pathophysiological and therapeutic effects. This study will be able to provide the potential therapeutic target of operation of a liver-to peripheral tissue-signaling loop to modulate metabolic inflammation and insulin sensitivity.

由肝脏脂代谢紊乱引发的肝脏及全身慢性低水平炎症是导致胰岛素抵抗、非酒精性脂肪性肝炎、2型糖尿病及肿瘤发生的关键。然而脂变肝细胞通过何种机制介导肝脏区域性免疫炎症反应及系统胰岛素抵抗尚不明确。胞外囊泡是细胞间生物信号分子传输的介质，能介导临近细胞及远处组织的炎症反应，也是疾病诊断和治疗的潜在靶标。前期研究发现肝细胞内TGFβ信号能促进肝细胞脂肪变性及炎症反应，并介导系统胰岛素抵抗，但机制不明。本课题通过体外实验明确TGFβ1协同游离脂肪酸介导肝细胞释放何种胞外囊泡；上述不同特征的胞外囊泡对肝细胞、Kupffer细胞、肝星状细胞、骨骼肌细胞、脂肪细胞及血管内皮细胞的表型有何影响；并通过体内实验将不同特征的胞外囊泡导入小鼠体内，观察肝细胞释放的胞外囊泡对介导肝脏区域性炎症反应及系统胰岛素抵抗的作用，为通过调控“肝脏-外周组织信号环路”干预肝脏及肝外组织脂代谢性炎症及系统胰岛素抵抗。

由肝脏脂代谢紊乱引发的肝脏及全身慢性低水平炎症是导致胰岛素抵抗、非酒精性脂肪性肝炎、2型糖尿病及肿瘤发生的关键。我们研究发现肝细胞内TGFβ信号能促进肝细胞脂肪变性及炎症反应，并介导系统胰岛素抵抗。通过体外实验明确了TGFβ1协同游离脂肪酸可介导肝细胞释放富含micRNA的胞外囊泡,并可与肝细胞、脂肪细胞、内皮细胞、心肌细胞相互作用，介导相应的病理生理改变；并发现TRIF是新的NASH肝纤维化调节因子，CREG能通过调控TAK1阻止肝脏缺血再灌注损伤，TUDCA能通过调控肠道菌群紊乱、保护肠屏障功能，阻止高脂饮食诱导的NASH。本项目在国家自然科学基金委资助下共发表论文17 篇，标注基金资助，其中SCI收录9篇，影响因子大于10分的论文2篇，被 Nature、Hepatology 等一流国际期刊他引 121 次以上，对于研发治疗非酒精性脂肪性肝炎、纤维化及癌变的药物提供的实验依据及靶点，在肝脏脂变、炎症、纤维化领域产生了广泛影响。培养硕士研究生6人，博士研究生5人，4人赴国外开展学术交流学习。项目组成员获得国家自然科学基金面上项目持续资助7项,湖北省科技创新重点项目1项。

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