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

doi:10.1016/j.isci.2020.100973

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 journal › Article › peer-review

6 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 language	English (US)
Article number	100973
Journal	iScience
Volume	23
Issue number	4
DOIs	https://doi.org/10.1016/j.isci.2020.100973
State	Published - Apr 24 2020
Externally published	Yes

Keywords

Diabetology
Genetics
Metabolomics
Specialized Functions of Cells

ASJC Scopus subject areas

General

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10.1016/j.isci.2020.100973

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@article{d5513119a4c44c528f1308901a486326,

title = "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. 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.",

keywords = "Diabetology, Genetics, Metabolomics, Specialized Functions of Cells",

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

note = "Funding Information: This work was supported by funding from National Heart, Lung, and Blood Institute grant 5R33HL120781-05 to S.K. G.M.P. is supported by KO1HL125751 , RO3HL141439 , and RO1HL142711 . X.-Y.X. was in part supported by American Heart Association SDG grant ( 11SDG7670007 ). We thank Partners Healthcare Personalized Medicine for the RNA-seq acquisition and analysis, in particular Dr. Sami Samir Amr and Mark J. Bowser for their support in the data analysis and submission, and Andrew Johnston for his contribution to the early stage of this project. Publisher Copyright: {\textcopyright} 2020 The Author(s)",

year = "2020",

month = apr,

day = "24",

doi = "10.1016/j.isci.2020.100973",

language = "English (US)",

volume = "23",

journal = "iScience",

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TY - JOUR

T1 - EDEM3 Modulates Plasma Triglyceride Level through Its Regulation of LRP1 Expression

AU - Xu, Yu Xin

AU - Peloso, Gina M.

AU - Nagai, Taylor H.

AU - Mizoguchi, Taiji

AU - Deik, Amy

AU - Bullock, Kevin

AU - Lin, Honghuang

AU - Musunuru, Kiran

AU - Yang, Qiong

AU - Vasan, Ramachandran S.

AU - Gerszten, Robert E.

AU - Clish, Clary B.

AU - Rader, Daniel

AU - Kathiresan, Sekar

N1 - Funding Information: This work was supported by funding from National Heart, Lung, and Blood Institute grant 5R33HL120781-05 to S.K. G.M.P. is supported by KO1HL125751 , RO3HL141439 , and RO1HL142711 . X.-Y.X. was in part supported by American Heart Association SDG grant ( 11SDG7670007 ). We thank Partners Healthcare Personalized Medicine for the RNA-seq acquisition and analysis, in particular Dr. Sami Samir Amr and Mark J. Bowser for their support in the data analysis and submission, and Andrew Johnston for his contribution to the early stage of this project. Publisher Copyright: © 2020 The Author(s)

PY - 2020/4/24

Y1 - 2020/4/24

N2 - 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.

AB - 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.

KW - Diabetology

KW - Genetics

KW - Metabolomics

KW - Specialized Functions of Cells

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DO - 10.1016/j.isci.2020.100973

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AN - SCOPUS:85082121952

SN - 2589-0042

VL - 23

JO - iScience

JF - iScience

IS - 4

M1 - 100973

ER -

EDEM3 Modulates Plasma Triglyceride Level through Its Regulation of LRP1 Expression

Abstract

Keywords

ASJC Scopus subject areas

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