Title: Receptor-Mediated ER Export of Lipoproteins Controls Lipid Homeostasis in Mice and Humans
Author: Xiao Wang, Huimin Wang, Bolin Xu, Dong Huang, Chao Nie, Longjun Pu, Gregory J.M. Zajac, Han Yan, Jingru Zhao, Fangyuan Shi, Brian T. Emmer, Jia Lu, Rui Wang, Xiaohui Dong, Jianye Dai, Wenjing Zhou, Chu Wang, Ge Gao, Yan Wang, Cristen Willer, Xiangfeng Lu, Yuangang Zhu, Xiao-Wei Chen
Abstract: Efficient delivery of specific cargos in vivo poses a major challenge to the secretory pathway, which shuttles products encodedby ～30% of the genome. Newly synthesized protein and lipid cargos embark on the secretorypathway via COPII-coated vesicles, assembled by the GTPase SAR1 on the endoplasmicreticulum (ER), but how lipid-carrying lipoproteins are distinguished from the generalprotein cargos in the ER and selectively secreted has not been clear. Here, we showthat this process is quantitatively governed by the GTPase SAR1B and SURF4, a high-efficiencycargo receptor. While both genes are implicated in lipid regulation in humans, hepaticinactivation 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 operatesa specialized, dosage-sensitive transport program for circulating lipids, while furthersuggesting a potential translation to treat atherosclerosis and related cardio-metabolicdiseases.