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Heterozygosity for a Loss-of-Function Mutation in GALNT2 Improves Plasma Triglyceride Clearance in Man
Department of Vascular Medicine, Academic Medical Center, Amsterdam 1105AZ, The Netherlands.
Linköping University, Department of Clinical and Experimental Medicine, Occupational and Environmental Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Centre, Occupational and Environmental Medicine Centre.
Section on Biological Chemistry, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892, USA.
Section on Biological Chemistry, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892, USA.
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2011 (English)In: Cell Metabolism, ISSN 1550-4131, Vol. 14, no 6, 811-8 p.Article in journal (Refereed) Published
Abstract [en]

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.
National Category
Medical and Health Sciences
URN: urn:nbn:se:liu:diva-73069DOI: 10.1016/j.cmet.2011.11.005ISI: 000298122400014PubMedID: 22152306OAI: 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 |

Available from: 2011-12-15 Created: 2011-12-15 Last updated: 2013-06-11Bibliographically approved

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Karlsson, HelenLjunggren, StefanLindahl, Mats
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