The Endoplasmic Reticulum Coat Protein II Transport Machinery Coordinates Cellular Lipid Secretion and Cholesterol Biosynthesis

Abstract

Background: Sar1 mediates the onward transport of ER cargo.Results: Sar1B promotes VLDL secretion, whereas Sar1A antagonizes this activity, and a deficit of both reduces cholesterol biosynthesis.Conclusion: Sar1B independently of and through its lipoprotein secretion function promotes the expression of genes regulating cholesterol biosynthesis.Significance: Sar1B-mediated transport activities contribute to both the functional integrity of the ER membrane and blood cholesterol levels.

Mea6 controls VLDL transport through the coordinated regulation of COPII assembly

“…Of note, the potential effects of COPII component deficiency on lipolysis could not be completely ruled out, and the exact role of COPII components in VLDL secretion needs to be examined using animal models. Nevertheless, Mea6 cKO and Sar1B mutations cause hepatic steatosis, likely resulting from retention of lipoprotein in the ER [17][18][19]. This provides more evidence that Mea6 regulates lipid transport through interaction with COPII subunits.…”

“…Sar1 binds to the ER membrane in its GTP-bound state and recruits the Sec23/24 heterodi-mer that forms the inner coat, which in turn recruits the outer coat proteins Sec13 and 31 to form the complex [14,15]. Sar1B mutations are associated with chylomicron retention disease and hepatic steatosis, likely resulting from retention of lipoproteins in the ER [17][18][19]. Thus, VLDL secretion likely involves Sar1.…”

Insights from human congenital disorders of intestinal lipid metabolism

“…Of note, if Sar1a could not compensate for loss of Sar1b in the gut, only limited data are, however, available regarding its contributions in the liver despite the fact that VLDL secretion was not substantially affected in CRD ( 220 ). Nevertheless, a recent study has provided strong evidence that Sar1b promotes the secretion of TG-rich Apo B-containing lipoproteins from the liver, which would neatly explain the counter-intuitive observation that some CRD children develop hepatic steatosis, despite severe intestinal fat malabsorption ( 221 ). Furthermore, SAR1b has been shown to be the predominantly expressed isoform in human jejunum and liver.…”

“…Furthermore, SAR1b has been shown to be the predominantly expressed isoform in human jejunum and liver. Although Sar1a antagonizes the lipoprotein secretion-promoting activity of Sar1b, both isoforms were noted to modulate the expression of genes encoding cholesterol biosynthetic enzymes and the synthesis of cholesterol de novo ( 221 ). It is noteworthy that Sar1b GTPase is not only central for the COPII responsible for the biosynthetic transport of proteins from the ER to the Golgi apparatus, but also for fusion of the specifi c CM transport vesicle, the preCM transport vesicle, with the Golgi ( 50, 54,222,223 ).…”

Studying lipoprotein trafficking in zebrafish, the case of chylomicron retention disease

“…1). In cultured hepatocytes, Sar1b knockdown causes a coordinated down-regulation of cholesterol synthetic genes, suggesting a parallel method to limit accumulation of free cholesterol in the setting of defective very low-density lipoprotein secretion [14].…”