Xu Yu-Xin, Peloso Gina M, Nagai Taylor H, Mizoguchi Taiji, Deik Amy, Bullock Kevin, Lin Honghuang, Musunuru Kiran, Yang Qiong, Vasan Ramachandran S, Gerszten Robert E, Clish Clary B, Rader Daniel, Kathiresan Sekar
Center for Genomic Medicine, Massachusetts General Hospital, Simches 5.500, 185 Cambridge St., Boston, MA 02114, USA.
Department of Biostatistics, Boston University School of Public Health, Boston, MA 02118, USA.
iScience. 2020 Apr 24;23(4):100973. doi: 10.1016/j.isci.2020.100973. Epub 2020 Mar 11.
Human genetics studies have uncovered genetic variants that can be used to guide biological research and prioritize molecular targets for therapeutic intervention for complex diseases. We have identified a missense variant (P746S) in EDEM3 associated with lower blood triglyceride (TG) levels in >300,000 individuals. Functional analyses in cell and mouse models show that EDEM3 deficiency strongly increased the uptake of very-low-density lipoprotein and thereby reduced the plasma TG level, as a result of up-regulated expression of LRP1 receptor. We demonstrate that EDEM3 deletion up-regulated the pathways for RNA and endoplasmic reticulum protein processing and transport, and consequently increased the cell surface mannose-containing glycoproteins, including LRP1. Metabolomics analyses reveal a cellular TG accumulation under EDEM3 deficiency, a profile consistent with individuals carrying EDEM3 P746S. Our study identifies EDEM3 as a regulator of blood TG, and targeted inhibition of EDEM3 may provide a complementary approach for lowering elevated blood TG concentrations.
人类遗传学研究发现了一些基因变异，这些变异可用于指导生物学研究，并为复杂疾病的治疗干预确定分子靶点的优先级。我们在超过30万名个体中发现了EDEM3基因中的一个错义变异（P746S），该变异与较低的血液甘油三酯（TG）水平相关。细胞和小鼠模型中的功能分析表明，由于LRP1受体表达上调，EDEM3缺陷会强烈增加极低密度脂蛋白的摄取，从而降低血浆TG水平。我们证明，EDEM3缺失会上调RNA以及内质网蛋白加工和运输的途径，从而增加细胞表面含甘露糖的糖蛋白，包括LRP1。代谢组学分析揭示了EDEM3缺陷时细胞内TG的积累，这与携带EDEM3 P746S的个体情况一致。我们的研究确定EDEM3是血液TG的调节因子，靶向抑制EDEM3可能为降低升高的血液TG浓度提供一种补充方法。
