文章基本信息

标题：EDEM3 Modulates Plasma Triglyceride Level through Its Regulation of LRP1 Expression
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作者：Yu-Xin Xu ; Gina M. Peloso ; Taylor H. Nagai 等
期刊名称：iScience
印刷版ISSN：2589-0042
出版年度：2020
卷号：23
期号：4
页码：1-33
DOI：10.1016/j.isci.2020.100973
语种：English
出版社：Elsevier
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