Artificial switching of the metabolic processing pathway of an etiologic factor, β2-microglobulin, by a “navigator” molecule
Artificial switching of the metabolic processing pathway of an etiologic factor, β2-microglobulin, by a “navigator” molecule
复制标题
通过“导航”分子人工切换病因因子β2-微球蛋白的代谢加工途径
DOI：
10.1016/j.jconrel.2020.07.041
复制
发表时间：
2020
影响因子：
10.8
通讯作者：
Yamaoka Tetsuji
中科院分区：
文献类型：
--
作者：
Kambe Yusuke;Koyashiki Kento;Hirano Yoshiaki;Harada-Shiba Mariko;Yamaoka Tetsuji
体内的代谢途径是高度特异性的。代谢途径的功能障碍触发其靶物质的积累。例如，肾衰竭导致血液中β2-微球蛋白水平升高，引起透析相关淀粉样变性。此前，我们提出了一种新的治疗概念，即通过人工切换代谢加工途径来消除代谢疾病的病因，并在培养细胞中测试了这一概念。然而，人工代谢转换在体内的可行性仍然未知。在这里，我们发现一种新开发的“导航”分子改变了小鼠β2-微球蛋白从肾脏到肝脏的代谢加工途径。人工代谢转换是通过导航器捕获致病因子，然后通过低密度脂蛋白受体将致病因子导向肝溶酶体来实现的。这些发现表明，基于导航的人工代谢转换可以成为治疗代谢紊乱引起的各种疾病的一种策略。
Metabolic pathways in the body are highly specific. Dysfunction of a metabolic pathway triggers the accumulation of its target substance. For example, kidney failure results in increased β2-microglobulin blood levels, causing dialysis-related amyloidosis. Previously, we proposed a novel therapeutic concept, that is a removal of an etiologic factor of metabolic disease by artificial switching of its metabolic processing pathway, and tested this concept using in cultured cells. However, the feasibility of artificial metabolic switchingin vivoremained unknown. Here, we show that a newly developed “navigator” molecule changes the metabolic processing pathway of β2-microglobulin from the kidney to the liver in mouse. The artificial metabolic switching is achieved by the capture of the etiologic factor by the navigator, which then steers the etiologic factor to hepatic lysosomes via low-density lipoprotein receptors. These findings demonstrate that navigator-based artificial metabolic switching can be a therapeutic strategy for various diseases caused by metabolic disorders.