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
PY - 2011
Y1 - 2011
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
U2 - https://doi.org/10.1016/j.cmet.2011.11.005
DO - https://doi.org/10.1016/j.cmet.2011.11.005
M3 - Article
C2 - 22152306
SN - 1550-4131
VL - 14
SP - 811
EP - 818
JO - Cell metabolism
JF - Cell metabolism
IS - 6
ER -