载脂蛋白AV通过mfge8调控脂质沉积心肌细胞脂肪酸摄取及机制探讨

Cardiac lipid accumulation is a major pathological manifestation of heart failure. We observed that apolipoprotein AV(apoAV) significantly reduce the cellular uptake of free fatty acid (FFA) and lipid accumulation in cardiomyocytes. Moreover, apoAV could significantly decrease the expression of milk fat globule epidermal growth factor 8(Mfge8), which has been demonstrated that could induce lipid accumulation in cardiomyocytes by promoting the cellular uptake of FFA. The effects of Mfge8 to induce lipid accumulation may relate to inhibition of the expression of FFA transported protein through peroxisome proliferators-activated receptor γ-PI3k/Akt signaling pathway. Therefore, we hypothesized apoAV may reduce lipid accumulation in cardiomyocytes by regulating the PPARγ-PI3k/Akt signaling through suppression of Mfge8 expression. In this study, we will focus to examine the effect of apoAV on the Mfge8-PPARγ-PI3k/Akt signaling pathway and identify the functional region of apoAV, in order to verify the mechanism by which apoAV regulates the cellular uptake of FFA in cardiomyocytes with lipid accumulation. This study is expected to provide a new strategy for controlling obesity-induced cardiac steatosis and congestive heart failure.

心肌细胞脂质沉积是心力衰竭常见的病理表现。我们前期证实：载脂蛋白AV（apoAV）可减少心肌细胞对游离脂肪酸（FFA）的摄取，改善脂质沉积，并下调乳脂球表皮生长因子8的表达（Mfge8）。最近研究发现，Mfge8可通过增加FFA摄取导致心肌细胞脂质沉积。Mfge8这一作用可能通过调控过氧化物酶体增值物激活受体γ（PPARγ）-PI3k/Akt途径，增加FFA摄取相关蛋白表达实现。由此推测：ApoAV可能通过抑制Mfge8的表达，影响PPARγ-PI3k/Akt途径及其下游信号通路，减少心肌细胞对FFA的摄取，改善脂质沉积。本项目拟从分子、细胞和动物水平观察apoAV对心肌细胞FFA摄取及Mfge8-PPARγ-PI3k/Akt信号通路的影响、鉴定apoAV发挥作用的关键结构，来明确apoAV调控心肌细胞FFA摄取的机制。本项目将扩展对apoAV的认识，并为肥胖人群心力衰竭的防治提供新思路。

肥胖作为糖尿病、心血管疾病及脂肪肝等多种疾病发生的独立危险因素，严重威胁着人类健康。心肌细胞脂质沉积是导致肥胖患者心肌肥厚、心力衰竭的重要机制之一。早期研究证实，载脂蛋白A5（apoA5）可显著增加肝脏内甘油三酯聚集，同时降低人脂肪细胞中甘油三酯水平。同时，本研究前期证明apoa5可显著降低心肌细胞脂质沉积状态下的甘油三酯水平，并下调乳脂球表皮生长因子8（Mfge8）的表达，但具体作用机制尚未明确。因此，本研究主要深入探讨apoa5对心肌脂质沉积的调控及分子机制。通过过表达apoa5能改善肥胖小鼠心脏功能，降低心肌脂质沉积，血浆甘油三酯和胆固醇含量降低；通过免疫共沉淀发现蛋白水平上Mfge8与apoa5有直接相互作用，apoa5干预后细胞内Mfge8、PPARγ、PI3K/Akt、FAT/CD36表达水平显著下调；apoa5通过Mfge8-PPARγ-PI3K/Akt-FAT/CD36调控心肌脂肪酸摄取，减少TG在脂质沉积状态下心肌细胞内的沉积。本研究深入探讨了apoa5改善肥胖小鼠心肌细胞脂质沉积中的作用机制，其有望成为将来肥胖人群心力衰竭防治的新靶点。