Receptor-Mediated ER Export of Lipoproteins Controls Lipid Homeostasis in Mice and Humans

Cell Metab. 2021 Feb 2;33(2):350-366.e7. doi: 10.1016/j.cmet.2020.10.020.

Xiao Wang ¹, Huimin Wang ², Bolin Xu ³, Dong Huang ³, Chao Nie ³, Longjun Pu ², Gregory J M Zajac ⁴, Han Yan ³, Jingru Zhao ², Fangyuan Shi ⁵, Brian T Emmer ⁶, Jia Lu ³, Rui Wang ², Xiaohui Dong ³, Jianye Dai ⁷, Wenjing Zhou ³, Chu Wang ⁸, Ge Gao ⁵, Yan Wang ⁹, Cristen Willer ⁴, Xiangfeng Lu ¹⁰, Yuangang Zhu ¹, Xiao-Wei Chen ¹¹

Affiliations

1 State Key Laboratory of Membrane Biology, Peking University, Beijing 100871, China; Institute of Molecular Medicine, Peking University, Beijing 100871, China.
2 Center for Life Sciences, Peking University, Beijing 100871, China.
3 Institute of Molecular Medicine, Peking University, Beijing 100871, China.
4 Department of Computational Medicine and Bioinformatics, Human Genetics, Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA.
5 Center for Bioinformatics, Peking University, Beijing 100871, China.
6 Department of Internal Medicine and Life Sciences Institute, University of Michigan, Ann Arbor, MI 48109, USA.
7 College of Chemical and Molecular Engineering, Peking University, Beijing 100871, China.
8 Center for Life Sciences, Peking University, Beijing 100871, China; College of Chemical and Molecular Engineering, Peking University, Beijing 100871, China.
9 Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Institute for Advanced Studies, Wuhan University, Wuhan 430072, China.
10 State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100037, China.
11 State Key Laboratory of Membrane Biology, Peking University, Beijing 100871, China; Institute of Molecular Medicine, Peking University, Beijing 100871, China; Center for Life Sciences, Peking University, Beijing 100871, China; PKU-Nanjing Institute of Translational Medicine, Nanjing 211800, China. Electronic address: xiaowei_chen@pku.edu.cn.

PMID: 33186557 DOI: 10.1016/j.cmet.2020.10.020

Abstract

Efficient delivery of specific cargos in vivo poses a major challenge to the secretory pathway, which shuttles products encoded by ∼30% of the genome. Newly synthesized protein and lipid cargos embark on the secretory pathway via COPII-coated vesicles, assembled by the GTPase SAR1 on the endoplasmic reticulum (ER), but how lipid-carrying lipoproteins are distinguished from the general protein cargos in the ER and selectively secreted has not been clear. Here, we show that this process is quantitatively governed by the GTPase SAR1B and SURF4, a high-efficiency cargo receptor. While both genes are implicated in lipid regulation in humans, hepatic inactivation of either mouse Sar1b or Surf4 selectively depletes plasma lipids to near-zero and protects the mice from atherosclerosis. These findings show that the pairing between SURF4 and SAR1B synergistically operates a specialized, dosage-sensitive transport program for circulating lipids, while further suggesting a potential translation to treat atherosclerosis and related cardio-metabolic diseases.

Keywords

COPII; cardio-metabolic disease; human genetics; lipid homeostasis; lipoprotein receptor; secretion.

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