Year: 2019
Type: article
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. 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.
Source: iScience
Language: English
Subfield: Cardiology and Cardiovascular Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $3,000
Awards: G1049408530, G1739371612, G1814678125, G266302070, G3473554580, Discovering lipoprotein lipase pathway variants that protect against CHD, Genetic determinants of triglyceride-rich lipoproteins to disentangle CHD risk, G5898969320, G6924877303, G8632520631, Whole genome sequences in ethnically diverse individuals to comprehensively characterize the genetic mechanisms of dyslipidemias
OpenAlex ID: W3012326314