摘要：SummaryHuman 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) inEDEM3associated 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 carryingEDEM3P746S. 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.Graphical AbstractDisplay OmittedHighlights•Genetic deficiency of EDEM3 leads to lower blood triglyceride (TG) level•EDEM3 deficiency increases VLDL uptake by up-regulating LRP1 receptor expression•Blood TG changes due to EDEM3 mutation correlate with the TG profile of EDEM3 KO cellsGenetics; Diabetology; Specialized Functions of Cells; Metabolomics
