EDEM3 Modulates Plasma Triglyceride Level through Its Regulation of LRP1 Expression

Yu Xin Xu, Gina M. Peloso, Taylor H. Nagai, Taiji Mizoguchi, Amy Deik, Kevin Bullock, Honghuang Lin, Kiran Musunuru, Qiong Yang, Ramachandran S. Vasan, Robert E. Gerszten, Clary B. Clish, Daniel Rader, Sekar Kathiresan

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

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.

Original languageEnglish (US)
Article number100973
JournaliScience
Volume23
Issue number4
DOIs
StatePublished - Apr 24 2020
Externally publishedYes

Keywords

  • Diabetology
  • Genetics
  • Metabolomics
  • Specialized Functions of Cells

ASJC Scopus subject areas

  • General

Fingerprint

Dive into the research topics of 'EDEM3 Modulates Plasma Triglyceride Level through Its Regulation of LRP1 Expression'. Together they form a unique fingerprint.

Cite this