TY - JOUR
T1 - Heterozygosity for a loss-of-function mutation in GALNT2 improves plasma triglyceride clearance in man
AU - Holleboom, Adriaan G.
AU - Karlsson, Helen
AU - Lin, Ruei Shiuan
AU - Beres, Thomas M.
AU - Sierts, Jeroen A.
AU - Herman, Daniel S.
AU - Stroes, Erik S.G.
AU - Aerts, Johannes M.
AU - Kastelein, John J.P.
AU - Motazacker, Mohammad M.
AU - Dallinga-Thie, Geesje M.
AU - Levels, Johannes H.M.
AU - Zwinderman, Aeilko H.
AU - Seidman, Jonathan G.
AU - Seidman, Christine E.
AU - Ljunggren, Stefan
AU - Lefeber, Dirk J.
AU - Morava, Eva
AU - Wevers, Ron A.
AU - Fritz, Timothy A.
AU - Tabak, Lawrence A.
AU - Lindahl, Mats
AU - Hovingh, G. Kees
AU - Kuivenhoven, Jan Albert
N1 - Funding Information:
We are indebted to the study participants and thank C.A. Koch, A.W. Schimmel, J. Coelho Amado de Azevedo, J. Peter, J. Legemate, A. van der Made, and B. van den Bogaard for their help facilitating this family study. We thank the Sanquin Blood Bank for providing control DNA samples, M. Nieuwdorp for his help designing the desialylation experiments, and Xenon Genetics for financing the collection of DNA. This study was supported by the European Union (FP6-2005-LIFESCIHEALTH-6; STREP contract number 037631), Fondation Leducq Transatlantic Networks of Excellence (2010), NWO Medium Investment Grant (40-00506-98-9001 to D.J.L.), and the Intramural Research Program of the National Institute of Dental and Craniofacial Research (NIDCR), National Institutes of Health. A.G.H. is supported by the Netherlands Organisation for Scientific Research (021.001.035). J.J.P.K. received the Lifetime Achievement Award of the Netherlands Heart Foundation (2010T082).
PY - 2011/12/7
Y1 - 2011/12/7
N2 - 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.
AB - 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.
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U2 - 10.1016/j.cmet.2011.11.005
DO - 10.1016/j.cmet.2011.11.005
M3 - Article
C2 - 22152306
AN - SCOPUS:82955239839
SN - 1550-4131
VL - 14
SP - 811
EP - 818
JO - Cell Metabolism
JF - Cell Metabolism
IS - 6
ER -