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Cell Metab. 2011 Dec 7;14(6):811-8. doi: 10.1016/j.cmet.2011.11.005.

Heterozygosity for a loss-of-function mutation in GALNT2 improves plasma triglyceride clearance in man.

Author information

1
Department of Vascular Medicine, Academic Medical Center, Amsterdam 1105AZ, The Netherlands.

Abstract

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.

PMID:
22152306
PMCID:
PMC3523677
DOI:
10.1016/j.cmet.2011.11.005
[Indexed for MEDLINE]
Free PMC Article

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