肝细胞受体syndecan-1通过flotillin-1介导饮食后乳糜残余物脂质代谢降解的分子机制

饮食后的脂代谢紊乱是导致动脉粥样硬化的一个重要原因。先前发现肝细胞受体syndecan-1在饮食后脂代谢降解过程中起重要作用，并通过脂筏依赖性的胞饮途径来实现，但其分子机制一直不明。课题前期研究发现flotillin-1（FLOT1）参与肝细胞syndecan-1介导的脂蛋白胞饮过程，及Src激酶为必需的调节因子。课题假设:Src激酶磷酸化FLOT1, 激活的FLOT1招募结合dynaminI/II 和c-Cbl, 并使它们被Src磷酸化激活; 激活后的FLOT1和dynaminI/II在受体-配体复合体的胞饮前体形成与内陷中起关键作用；激活后的c-Cbl可使syndecan-1泛素化而诱导其降解。研究还发现FLOT1在II型糖尿病小鼠肝脏中的表达显著被抑制，体内肝细胞表达腺病毒携带的FLOT1基因显著改善II型糖尿病伴随的脂质代谢紊乱。研究将探讨syndecan-1介导饮食后脂代谢的机制

Postprandial dyslipidemia is one of the most important factors resulting in atherosclerosis. Previously, we and then others found that syndecan-1, a hepatic receptor, plays a critical role in the lipoprotein catabolism after fatty meals via endocytosis, of which, however, the molecular mechanism is still unclear. In the present preliminary study, we found that flotillin-1(FLOT1) is involving the syndecan-1-mediated endocytosis of lipoproteins, which requires Src kinase. Thus we hypothsize that Src kinase phosphorylates FLOT1, and that activated FLOT1 recruits dynamin I/II and c-CbI that might be phosphorylated by Src as well. Furthermore, activated FLOT1 and dynamin I/II may play key roles in the formation of pre-endosome and in followed invagination during endocytosis. Meanwhile, activated c-CbI may link the ubiquitins to syndecan-1 molecules, therefore eliciting the degradation of receptor-ligand complex in lysosome. More importantly, the hepatic FLOT1 expression was found to be substantially inhibited in type 2 diabetic mice, and we speculate that in vivo expression of FLOT1 protein through caudal injection of adenovirus particles carrying flot1 gene into diabetic mice may significantly ameliorate hypertriglyceridemia under T2DM. The current study is expected to provide essential scientific evidence for unraveling the molecular mechanisem underlying the syndecan-1-mediated catabolism of postprandial remnant lipoproteins.