EDEM3 Modulates Plasma Triglyceride Level through Its Regulation of LRP1 Expression
| Autor: | Qiong Yang, Gina M. Peloso, Sekar Kathiresan, Yu-Xin Xu, Ramachandran S. Vasan, Taylor H. Nagai, Daniel J. Rader, Kevin Bullock, Robert E. Gerszten, Honghuang Lin, Taiji Mizoguchi, Kiran Musunuru, Clary B. Clish, Amy Deik |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Cell 02 engineering and technology Article chemistry.chemical_compound 03 medical and health sciences 0302 clinical medicine Metabolomics Genetics medicine lcsh:Science Receptor 030304 developmental biology chemistry.chemical_classification 0303 health sciences Multidisciplinary Triglyceride Chemistry Endoplasmic reticulum RNA Diabetology Specialized Functions of Cells 021001 nanoscience & nanotechnology LRP1 3. Good health Cell biology 030104 developmental biology medicine.anatomical_structure lcsh:Q 0210 nano-technology Glycoprotein 030217 neurology & neurosurgery Lipoprotein |
| Zdroj: | iScience, Vol 23, Iss 4, Pp-(2020) iScience |
| ISSN: | 2589-0042 |
| Popis: | 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. Graphical Abstract Highlights • Genetic deficiency of EDEM3 leads to lower blood triglyceride (TG) level • EDEM3 deficiency increases VLDL uptake by up-regulating LRP1 receptor expression • Blood TG changes due to EDEM3 mutation correlate with the TG profile of EDEM3 KO cells Genetics; Diabetology; Specialized Functions of Cells; Metabolomics |
| Databáze: | OpenAIRE |
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