FAT/CD36途径介导的代谢性炎症发生与非酒精性脂肪性肝病

Metabolic inflammation, triggered by overload of nutrients and metabolic surplus shares similar signalling pathway with classical inflammatory response. Pattern recognition receptors (PPR) play important roles in linking inflammation and metabolism. Fatty acid translocase (FAT/CD36),one of PPR belongs to the class B scavenger receptor family and has an important function in uptake of fatty acids in the liver. It has been shown that FAT/CD36 is involved in the pathogenesis of nonalcoholic fatty liver disease (NAFLD)by inceasing hepatic fatty acid uptake. However, the role of FAT/CD36 in regulating inflammatory responses in NAFLD remains unclear. .Our previous work has demonstrated that high fat diet increased liver FAT/CD36 expression which transported more fatty acids from blood to liver resulting in NAFLD and inflammatory response in C57BL/6J mice. Interestingly, the hepatic lipid accumulation and the inflammatory response were reduced by the deletion of FAT/CD36 in a mice model. .We propose that hepatic FAT/CD36 upregulation is significantly associated with metabolic inflammation which may contribute to fat accumulation in liver. Under metabolic disorders, the increased oxidized LDL(ox-LDL) and fatty acids stimulate CD36 protein expression in liver which activates NF-κB inflammatory signaling pathway by recuiting protein kinases, c-Jun N-terminal kinase(JNK)and Toll-like receptor(TLR) 4/6 complex ..This project is designed ,in cultured hepatic cells and the FAT/CD36 gene knockout mouse model, to investigate 1) whether FAT/CD36 activation by fatty acids or ox-LDL mediates inflammatory response and its underlying mechanism;2) whether the metabolic inflammation involves in the progression of NAFLD.

代谢性炎症主要指营养物和代谢过剩所触发的炎症过程，而模式识别受体是连接炎症与代谢之间的重要桥梁。课题组前期发现：高脂或炎症等病理状态下，模式识别受体脂肪酸转运酶（FAT/CD36）在肝脏表达增高并可转运大量脂肪酸到细胞内积聚形成非酒精性脂肪性肝病(NAFLD)；同时也观察到它与肝脏炎症反应程度密切相关。然而，FAT/CD36介导肝脏代谢性炎症产生的分子机制尚不清楚。我们推测：高脂状态下肝脏FAT/CD36表达增高会启动其胞内信号传导，与蛋白激酶分子、Toll样受体、JNK激酶之间相互关联而促进NF-κB炎症信号通路活化；代谢性炎症的产生会进一步促进肝FAT/CD36蛋白表达，加重炎症发生及NAFLD发展。.本项目拟应用实验室已建立的多种体内外实验模型和技术，深入探讨高脂状态下FAT/CD36介导肝脏代谢性炎症产生的可能分子机制及其在NAFLD发生、发展中的作用，为脂肪肝的防治提供理论依据。

代谢性炎症在NAFLD发生、发展中的起了非常重要的作用。然而，在营养物质和代谢过剩时，肝脏内的代谢性炎症是如何被启动？在炎症和肝脏脂质代谢之间起着桥梁作用的重要因子是哪些、其调控机制又是怎样？代谢性炎症又是如何影响肝脏脂代谢信号传导通路从而加重脂质在肝脏的积聚？这些问题尚不清楚。课题组前期发现：高脂或炎症等病理状态下，模式识别受体脂肪酸转运酶（FAT/CD36）在肝脏表达增高并可转运大量脂肪酸到细胞内积聚形成非酒精性脂肪性肝病(NAFLD)；同时也观察到它与肝脏炎症反应程度密切相关。然而，FAT/CD36介导肝脏代谢性炎症产生的分子机制尚不清楚。我们推测：高脂状态下肝脏FAT/CD36表达增高会启动其胞内信号传导，与蛋白激酶分子、Toll样受体、JNK激酶之间相互关联而促进NF-κB炎症信号通路活化；代谢性炎症的产生会进一步促进肝FAT/CD36蛋白表达，加重炎症发生及NAFLD发展。本项目拟应用实验室已建立的多种体内外实验模型和技术，深入探讨高脂状态下FAT/CD36介导肝脏代谢性炎症产生的可能分子机制及其在NAFLD发生、发展中的作用，为脂肪肝的防治提供理论依据。.通过本项目的一系列体内外实验，我们发现：①高脂饮食或棕榈酸可以上调肝脏组织或肝细胞／巨噬细胞的CD36表达，促进CD36／TLR4共聚体形成，激活肝脏组织或肝脏细胞的炎症反应；②CD36在肝脏超表达可以激活肝组织炎症，加重肝脏脂质积聚；③肝细胞中CD36缺失可能通过减少ROS产量来抑制核内HDAC2表达，从而上调了MCP-1启动子区域组蛋白的乙酰化水平，导致MCP-1基因的表达增加，诱导巨噬细胞的浸润，也可以在体内导致肝组织炎症反应发生。我们的研究表明： FAT/CD36 在肝脏中的正常表达对于维持肝脏的脂代谢平衡及炎症应激状态至关重要，而肝脏FAT/CD36 基因或蛋白的过高或过低/缺失表达均能通过不同机制诱发肝脏脂质积聚和炎症的加重。因此，单纯在转录或翻译水平去干预肝脏FAT/CD36 蛋白的表达，对防治由FAT/CD36 介导的NAFLD 的发生和发展，不是最佳选择。为今后进一步从FAT/CD36 蛋白定位和功能的角度去深入研究和理解CD36对NAFLD 的发生发展相关机制、寻找有效的治疗手段都具有重要意义。