Quantitative Control of Endoplasmic Reticulum Exiting of Lipid Cargos Specified by SAR1B

Proteins and lipids are two major classes of transport cargos serving specific physiological functions.How these distinct biomolecules are differentially sorted through the secretory pathway,however,remains unknown.Here we report that the small GTPase SAR1B,mutated in the Chylomicron Retention Disease(CMRB),plays a rate-limiting role in specifying lipid secretion from the endoplasmic reticulum(ER).Loss of hepatic SAR1B ablated secretion of bulk lipid carried by the Apo B-containing lipoproteins(VLDLs),but didn’t affect transport of proteins including Albumin,LDLR,and PCSK9.Genetic analysis revealed that SAR1B functions independently of LDLR or PCSK9.SAR1B deficiency imposed a quantitative blockade in ER exiting of lipidated Apo B,whereas the lipid-free form of Apo B escaped this blockade.Furthermore,loss of hepatic SAR1B prevented pathogenic dyslipidemia and atherosclerosis induced by high fat feeding combined with LDLR deficiency.Thus,our study supported a"gatekeeper"role of SAR1B in a specialized transport ...Proteins and lipids are two major classes of transport cargos serving specific physiological functions.How these distinct biomolecules are differentially sorted through the secretory pathway,however,remains unknown.Here we report that the small GTPase SAR1B,mutated in the Chylomicron Retention Disease(CMRB),plays a rate-limiting role in specifying lipid secretion from the endoplasmic reticulum(ER).Loss of hepatic SAR1B ablated secretion of bulk lipid carried by the Apo B-containing lipoproteins(VLDLs),butInstitute of Biophysics, Chinese Academy of Sciences、National Laboratory of Biomacromolecules、State Key Laboratory of Biotherapy