Drosophila Lipophorin Receptors Recruit the Lipoprotein LTP to the Plasma Membrane to Mediate Lipid Uptake

Lipophorin, the main Drosophila lipoprotein, circulates in the hemolymph transporting lipids between organs following routes that must adapt to changing physiological requirements. Lipophorin receptors expressed in developmentally dynamic patterns in tissues such as imaginal discs, oenocytes and ovaries control the timing and tissular distribution of lipid uptake. Using an affinity purification strategy, we identified a novel ligand for the lipophorin receptors, the circulating lipoprotein Lipid Transfer Particle (LTP). We show that specific isoforms of the lipophorin receptors mediate the extracellular accumulation of LTP in imaginal discs and ovaries. The interaction requires the LA-1 module in the lipophorin receptors and is strengthened by a contiguous region of 16 conserved amino acids. Lipophorin receptor variants that do not interact with LTP cannot mediate lipid uptake, revealing an essential role of LTP in the process. In addition, we show that lipophorin associates with the lipophorin receptors and with the extracellular matrix through weak interactions. However, during lipophorin receptor-mediated lipid uptake, LTP is required for a transient stabilization of lipophorin in the basolateral plasma membrane of imaginal disc cells. Together, our data suggests a molecular mechanism by which the lipophorin receptors tether LTP to the plasma membrane in lipid acceptor tissues. LTP would interact with lipophorin particles adsorbed to the extracellular matrix and with the plasma membrane, catalyzing the exchange of lipids between them.

脂脂蛋白（Lipophorin）是果蝇（Drosophila）体内的主要脂蛋白，可在血淋巴（hemolymph）中循环，于各器官间转运脂质，其转运路径需随生理需求的变化做出适应性调整。脂脂蛋白受体在成虫盘、成脂细胞以及卵巢等组织中以发育动态模式表达，可调控脂质摄取的时序与组织分布。
本研究采用亲和纯化策略，鉴定出脂脂蛋白受体的一种新型配体——循环脂蛋白脂质转运颗粒（Lipid Transfer Particle, LTP）。实验证实，脂脂蛋白受体的特定亚型可介导脂质转运颗粒在成虫盘与卵巢中的胞外积累。该相互作用依赖于脂脂蛋白受体上的LA-1结构域（LA-1 module），并由一段连续的16个保守氨基酸序列增强结合强度。无法与脂质转运颗粒结合的脂脂蛋白受体变体无法介导脂质摄取，这表明脂质转运颗粒在该过程中发挥不可或缺的关键作用。
此外，本研究发现脂脂蛋白可通过弱相互作用与脂脂蛋白受体及细胞外基质结合。但在脂脂蛋白受体介导的脂质摄取过程中，脂脂蛋白在成虫盘细胞基底外侧质膜的瞬时稳定依赖于脂质转运颗粒的参与。
综上，本研究结果揭示了一种分子机制：脂脂蛋白受体可在脂质摄取组织中将脂质转运颗粒锚定至质膜；脂质转运颗粒可与吸附于细胞外基质及质膜的脂脂蛋白颗粒结合，从而催化二者间的脂质交换。