Heterozygosity for a Loss-of-Function Mutation in GALNT2 Improves Plasma Triglyceride Clearance in Man

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 li...

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Veröffentlicht in:Cell metabolism 2011-12, Vol.14 (6), p.811-818
Hauptverfasser: Holleboom, Adriaan G., Karlsson, Helen, Lin, Ruei-Shiuan, Beres, Thomas M., Sierts, Jeroen A., Herman, Daniel S., Stroes, Erik S.G., Aerts, Johannes M., Kastelein, John J.P., Motazacker, Mohammad M., Dallinga-Thie, Geesje M., Levels, Johannes H.M., Zwinderman, Aeilko H., Seidman, Jonathan G., Seidman, Christine E., Ljunggren, Stefan, Lefeber, Dirk J., Morava, Eva, Wevers, Ron A., Fritz, Timothy A., Tabak, Lawrence A., Lindahl, Mats, Hovingh, G. Kees, Kuivenhoven, Jan Albert
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Sprache:eng
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Zusammenfassung: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. [Display omitted] ▸ GALNT2, a gene identified by GWAS, modulates lipid metabolism via apoC-III ▸ A functional mutation in GALNT2 is associated with improved triglyceride clearance ▸ Carriers of the mutation are characterized by attenuated glycosylation of apoC-III ▸ Desialylation of apoC-III decreases its potential to inhibit lipoprotein lipase
ISSN:1550-4131
1932-7420
1932-7420
DOI:10.1016/j.cmet.2011.11.005