The Endoplasmic Reticulum COPII-Vesicle Transport Machinery Coordinates Cellular Lipid Secretion and Cholesterol Biosynthesis

Lee G D Fryer, Bethan Jones, Emma J Duncan, Claire E Hutchison, Tozen Ozkan, Paul A Williams, Olivia Alder, Max Nieuwdorp, Anna K Townley, Arjen R Mensenkamp, David J Stephens, Geesje M Dallinga-Thie, Carol C Shoulders

Research output: Contribution to journalArticle (Academic Journal)peer-review

29 Citations (Scopus)

Abstract

Triglycerides and cholesterol are essential for life in most organisms. Triglycerides serve as the principal energy-storage depot and, where vascular systems exist, as a means of energy transport; while cholesterol is essential for the functional integrity of all cellular membrane systems. The endoplasmic reticulum (ER) is the site of secretory lipoprotein production and de novo cholesterol synthesis, yet little is known about how these activities are coordinated with each other, or with the activity of the COPII machinery, which transports ER cargo to the Golgi. The Sar1B component of this machinery is mutated in Chylomicron Retention Disorder (CMRD), indicating that this Sar1 isoform secures delivery of dietary lipids into the circulation. However, it is not known why some CMRD patients develop hepatic steatosis, despite impaired intestinal fat malabsorption; and why very severe hypocholesterolemia develops in this condition. Here we show that Sar1B also promotes hepatic apolipoprotein (apo)B lipoprotein secretion, and that this promoting activity is coordinated with the processes regulating apoB expression and the transfer of triglycerides/cholesterol moieties onto this large lipid transport protein. We also show thatalthough Sar1A antagonizes Sar1B's lipoprotein-secretion-promoting activity, both isoforms modulate the expression of genes encoding cholesterol biosynthetic enzymes and the synthesis of cholesterol de novo. These results not only establish that Sar1B promotes the secretion of hepatic lipids but also adds regulation of cholesterol synthesis to Sar1B's repertoire of transport functions.
Original languageEnglish
JournalJournal of Biological Chemistry
DOIs
Publication statusPublished - 13 Dec 2013

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