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
Affiliations
Yu-Xin Xu
Center for Genomic Medicine, Massachusetts General Hospital, Simches 5.500, 185 Cambridge St., Boston, MA 02114, USA; Corresponding author
Gina M. Peloso
Department of Biostatistics, Boston University School of Public Health, Boston, MA 02118, USA
Taylor H. Nagai
Center for Genomic Medicine, Massachusetts General Hospital, Simches 5.500, 185 Cambridge St., Boston, MA 02114, USA
Taiji Mizoguchi
Center for Genomic Medicine, Massachusetts General Hospital, Simches 5.500, 185 Cambridge St., Boston, MA 02114, USA
Amy Deik
The Metabolomics Program, Broad Institute, Cambridge, MA 02142, USA
Kevin Bullock
The Metabolomics Program, Broad Institute, Cambridge, MA 02142, USA
Honghuang Lin
Section of Computational Biomedicine, Department of Medicine, Boston University School of Medicine, Boston, MA 02118, USA
Kiran Musunuru
Cardiovascular Institute, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
Qiong Yang
Department of Biostatistics, Boston University School of Public Health, Boston, MA 02118, USA
Ramachandran S. Vasan
Preventive Medicine and Epidemiology, Boston University School of Medicine, Boston, MA 02118, USA; Framingham Heart Study of the NHLBI and Boston University School of Medicine, Framingham, MA 01702, USA
Robert E. Gerszten
Division of Cardiovascular Medicine, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA
Clary B. Clish
The Metabolomics Program, Broad Institute, Cambridge, MA 02142, USA
Daniel Rader
Institute for Translational Medicine and Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
Sekar Kathiresan
Center for Genomic Medicine, Massachusetts General Hospital, Simches 5.500, 185 Cambridge St., Boston, MA 02114, USA; Corresponding author, Center for Genomic Medicine and Cardiovascular Research Center, Massachusetts General Hospital, Simches 5.252, 185 Cambridge St., Boston, MA 02114, USA
Summary: 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. : Genetics; Diabetology; Specialized Functions of Cells; Metabolomics Subject Areas: Genetics, Diabetology, Specialized Functions of Cells, Metabolomics