中科院学者Cell Res解析脂肪肝发病机理

　　

　　脂肪肝是由于肝细胞内脂肪堆积过多所导致的病变，已成为影响人类健康的常见病。极低密度脂蛋白（VLDL）的组装和分泌缺陷是影响肝脏和血液脂代谢平衡的重要原因，但有关VLDL的组装和分泌，并运输到血液中的具体机制目前还不清楚。

　　中国科学院遗传与发育生物学研究所许执恒研究组发现高脂食物可诱导MEA6的表达。通过制备MEA6基因的条件性敲除小鼠模型，他们发现在肝脏中特异敲除MEA6可导致严重的脂肪肝，以及血浆中各种脂类的显著降低。结合细胞生物学、蛋白质组学、脂组学和生化手段，他们对MEA6在脂肪代谢过程中的分子机制进行了系统性研究，发现MEA6和内质网COPⅡ复合体（COPⅡ负责内质网到高尔基体的囊泡运输）中的多个组分相互作用。进一步的研究表明，MEA6是调控COPⅡ复合物组装的关键因子，为形成大的囊泡提供支撑，从而在VLDL的分泌过程中起到了重要作用。该研究为探索VLDL分泌的分子机制及脂肪肝的发病机制打下了重要基础。

　　该研究结果于6月17日发表在Cell Research (Cell Res. 2016 Jun 17. doi: 10.1038/cr.2016.75)上，许执恒实验室的副研究员王雅清、博士生刘亮为该文的共同第一作者。该研究得到了国家自然科学基金和中国科技部“973”项目的支持。

 

MEA6和COPII相互作用并调控VLDL分泌运输的模式图

原文摘要：

Mea6 controls VLDL transport through the coordinated regulation of COPII assembly

Lipid accumulation, which may be caused by the disturbance in very low density lipoprotein (VLDL) secretion in the liver, can lead to fatty liver disease. VLDL is synthesized in endoplasmic reticulum (ER) and transported to Golgi apparatus for secretion into plasma. However, the underlying molecular mechanism for VLDL transport is still poorly understood. Here we show that hepatocyte-specific deletion of meningioma-expressed antigen 6 (Mea6)/cutaneous T cell lymphoma-associated antigen 5C (cTAGE5C) leads to severe fatty liver and hypolipemia in mice. Quantitative lipidomic and proteomic analyses indicate that Mea6/cTAGE5 deletion impairs the secretion of different types of lipids and proteins, including VLDL, from the liver. Moreover, we demonstrate that Mea6/cTAGE5 interacts with components of the ER coat protein complex II (COPII) which, when depleted, also cause lipid accumulation in hepatocytes. Our findings not only reveal several novel factors that regulate lipid transport, but also provide evidence that Mea6 plays a critical role in lipid transportation through the coordinated regulation of the COPII machinery.Cell Research advance online publication 17 June 2016; doi:10.1038/cr.2016.75.