Heterozygosity for a Loss-of-Function Mutation in GALNT2 Improves Plasma Triglyceride Clearance in Man
2011 (English)In: Cell Metabolism, ISSN 1550-4131, Vol. 14, no 6, 811-8 p.Article in journal (Refereed) Published
Genome-wide association studies have identified GALNT2 as a candidate gene in lipid metabolism, but it is not known how the encoded enzyme ppGalNAc-T2, which contributes to the initiation of mucin-type O-linked glycosylation, mediates this effect. In two probands with elevated plasma high-density lipoprotein cholesterol and reduced triglycerides, we identified a mutation in GALNT2. It is shown that carriers have improved postprandial triglyceride clearance, which is likely attributable to attenuated glycosylation of apolipoprotein (apo) C-III, as observed in their plasma. This protein inhibits lipoprotein lipase (LPL), which hydrolyses plasma triglycerides. We show that an apoC-III-based peptide is a substrate for ppGalNAc-T2 while its glycosylation by the mutant enzyme is impaired. In addition, neuraminidase treatment of apoC-III which removes the sialic acids from its glycan chain decreases its potential to inhibit LPL. Combined, these data suggest that ppGalNAc-T2 can affect lipid metabolism through apoC-III glycosylation, thereby establishing GALNT2 as a lipid-modifying gene.
Place, publisher, year, edition, pages
Elsevier, 2011. Vol. 14, no 6, 811-8 p.
Medical and Health Sciences
IdentifiersURN: urn:nbn:se:liu:diva-73069DOI: 10.1016/j.cmet.2011.11.005ISI: 000298122400014PubMedID: 22152306OAI: oai:DiVA.org:liu-73069DiVA: diva2:465755
Funding agencies|European Union| FP6-2005-LIFESCIHEALTH-6 037631 |Fondation Leducq Transatlantic Networks of Excellence||NWO| 40-00506-98-9001 |National Institute of Dental and Craniofacial Research (NIDCR), National Institutes of Health||Netherlands Organisation for Scientific Research| 021.001.035 |Netherlands Heart Foundation| 2010T082 |2011-12-152011-12-152013-06-11Bibliographically approved