PT  - JOURNAL ARTICLE
AU  - Yu-Xin Xu
AU  - Gina M. Peloso
AU  - Taylor H. Nagai
AU  - Taiji Mizoguchi
AU  - Amy Deik
AU  - Kevin Bullock
AU  - Honghuang Lin
AU  - Kiran Musunuru
AU  - Qiong Yang
AU  - Ramachandran S. Vasan
AU  - Robert E. Gerszten
AU  - Clary B. Clish
AU  - Daniel Rader
AU  - Sekar Kathiresan
TI  - EDEM3 modulates plasma triglyceride level through its regulation of LRP1 expression
AID  - 10.1101/742353
DP  - 2019 Jan 01
TA  - bioRxiv
PG  - 742353
4099  - http://biorxiv.org/content/early/2019/08/31/742353.short
4100  - http://biorxiv.org/content/early/2019/08/31/742353.full
AB  - 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 and metabolic conditions. 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 ER 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 with 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.