title: The endoplasmic reticulum coat protein II transport machinery coordinates cellular lipid secretion and cholesterol biosynthesis.
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. Cholesterol is essential for the functional integrity of all cellular membrane systems. The endoplasmic reticulum 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 endoplasmic reticulum cargo to the Golgi. The Sar1B component of this machinery is mutated in chylomicron retention disorder, indicating that this Sar1 isoform secures delivery of dietary lipids into the circulation. However, it is not known why some patients with chylomicron retention disorder 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 that although Sar1A antagonizes the lipoprotein secretion-promoting activity of Sar1B, 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.
authors: From the Endocrinology Centre, William Harvey Research Institute, Queen Mary University of London and Barts and The London School of Medicine and Dentistry, Charterhouse Square, London EC1M 6BQ, United Kingdom.
authors: Lee G D
authors: LG
authors: Fryer
authors: Bethan
authors: B
authors: Jones
authors: Emma J
authors: EJ
authors: Duncan
authors: Claire E
authors: CE
authors: Hutchison
authors: Tozen
authors: T
authors: Ozkan
authors: Paul A
authors: PA
authors: Williams
authors: Olivia
authors: O
authors: Alder
authors: Max
authors: M
authors: Nieuwdorp
authors: Anna K
authors: AK
authors: Townley
authors: Arjen R
authors: AR
authors: Mensenkamp
authors: David J
authors: DJ
authors: Stephens
authors: Geesje M
authors: GM
authors: Dallinga-Thie
authors: Carol C
authors: CC
authors: Shoulders
mesh_terms: D001055:Apolipoproteins B / Q000235:genetics / Q000378:metabolism*; D022181:COP-Coated Vesicles / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D002784:Cholesterol / Q000096:biosynthesis* / Q000235:genetics; D004721:Endoplasmic Reticulum / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D006056:Golgi Apparatus / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D006801:Humans; D006995:Hypobetalipoproteinemias / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D050356:Lipid Metabolism; D008055:Lipids / Q000235:genetics; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008286:Malabsorption Syndromes / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D020559:Monomeric GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D033921:Vesicular Transport Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D001055:Apolipoproteins B; D008055:Lipids; D033921:Vesicular Transport Proteins; D002784:Cholesterol; C493083:SAR1A protein, human; C513282:SAR1B protein, human; D020559:Monomeric GTP-Binding Proteins
keywords: Apolipoproteins; Cholesterol Regulation; Endoplasmic Reticulum (ER); Lipoprotein Secretion; Transcriptomics