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 |
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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.
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▸ 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 |
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ISSN: | 1550-4131 1932-7420 1932-7420 |
DOI: | 10.1016/j.cmet.2011.11.005 |