New insights into the role of glycosylation in lipoprotein metabolism.

PURPOSE OF REVIEW: Human genetics has provided new insights into the role of protein glycosylation in regulating lipoprotein metabolism. Here we review these new developments and discuss the biological insights they provide.

RECENT FINDINGS: Case descriptions of patients with congenital defects in N-glycosylation (CDG-I) frequently describe a distinct hypocholesterolemia in these rare multisystem clinical syndromes. Two novel CDGs with disturbed Golgi homeostasis and trafficking defects result in mixed glycosylation disorders, hepatic steatosis and hypercholesterolemia. In addition, the presence of particular N-glycans is essential for physiological membrane expression of scavenger receptor B1 and for adequate lipolytic activity of endothelial lipase. GalNAc-T2, a specific O-glycosyl transferase, was found to be a direct modulator of HDL metabolism across mammals, validating its relationship with HDL-c found in genome-wide association studies. Furthermore, genetic variation in ASGR1, the major subunit of the asialoglycoprotein receptor (ASGPR), was found to be associated with a reduction in LDL-c and risk of coronary artery disease.

SUMMARY: Protein glycosylation plays an important regulatory role in lipoprotein metabolism. Greater insight into how protein glycosylation regulates lipoprotein metabolism could provide novel approaches for the treatment of dyslipidemia.