EDEM3 modulates plasma triglyceride level through its regulation of LRP1 expression

Abstract

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.3

Bi-allelic variants in the ER quality-control mannosidase gene EDEM3 cause a congenital disorder of glycosylation

“…A low-frequency EDEM3 missense variant in the protease-associated domain (rs78444298, p.Pro746Ser, minor allele frequency $1.5%) was associated with an approximately 5% decrease in triglyceride levels. 40 In our subjects for whom fasting triglyceride levels are available (Table S1), all triglyceride measurements were within the normal range. This most likely reflects the multiple metabolic pathways influencing triglyceride levels and makes the use of triglycerides as a diagnostic marker for EDEM3-CDG challenging.…”