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

Adriaan G. Holleboom; Helen Karlsson; Ruei-Shiuan Lin; Thomas M. Beres; Jeroen A. Sierts; Daniel S. Herman; Erik S. G. Stroes; Johannes M. Aerts; John J. P. Kastelein; Mohammad M. Motazacker; Geesje M. Dallinga-Thie; Johannes H. M. Levels; Aeilko H. Zwinderman; Jonathan G. Seidman; Christine E. Seidman; Stefan Ljunggren; Dirk J. Lefeber; Eva Morava; Ron A. Wevers; Timothy A. Fritz; Lawrence A. Tabak; Mats Lindahl; G. Kees Hovingh; Jan Albert Kuivenhoven

doi:10.1016/j.cmet.2011.11.005

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

Adriaan G. Holleboom, Helen Karlsson, Ruei-Shiuan Lin, Thomas M. Beres, Jeroen A. Sierts, Daniel S. Herman, Erik S. G. Stroes, Johannes M. Aerts, John J. P. Kastelein, Mohammad M. Motazacker, Geesje M. Dallinga-Thie, Johannes H. M. Levels, Aeilko H. Zwinderman, Jonathan G. Seidman, Christine E. Seidman, Stefan Ljunggren, Dirk J. Lefeber, Eva Morava, Ron A. Wevers, Timothy A. FritzLawrence A. Tabak, Mats Lindahl, G. Kees Hovingh^*, Jan Albert Kuivenhoven

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

72 Citations (Scopus)

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.

Original language	English
Pages (from-to)	811-818
Number of pages	8
Journal	Cell metabolism
Volume	14
Issue number	6
DOIs	https://doi.org/10.1016/j.cmet.2011.11.005
Publication status	Published - 7-Dec-2011

Keywords

APOLIPOPROTEIN-C-III
2-DIMENSIONAL GEL-ELECTROPHORESIS
ANGIOPOIETIN-LIKE PROTEIN-3
LIPOPROTEIN-LIPASE S447X
RICH LIPOPROTEINS
MASS-SPECTROMETRY
HEPATIC-UPTAKE
GLYCOSYLATION
METABOLISM
APOPROTEINS

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10.1016/j.cmet.2011.11.005

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Holleboom, A. G., Karlsson, H., Lin, R-S., Beres, T. M., Sierts, J. A., Herman, D. S., Stroes, E. S. G., Aerts, J. M., Kastelein, J. J. P., Motazacker, M. M., Dallinga-Thie, G. M., Levels, J. H. M., Zwinderman, A. H., Seidman, J. G., Seidman, C. E., Ljunggren, S., Lefeber, D. J., Morava, E., Wevers, R. A., ... Kuivenhoven, J. A. (2011). Heterozygosity for a loss-of-function mutation in GALNT2 improves plasma triglyceride clearance in man. Cell metabolism, 14(6), 811-818. https://doi.org/10.1016/j.cmet.2011.11.005

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. / Heterozygosity for a loss-of-function mutation in GALNT2 improves plasma triglyceride clearance in man. In: Cell metabolism. 2011 ; Vol. 14, No. 6. pp. 811-818.

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title = "Heterozygosity for a loss-of-function mutation in GALNT2 improves plasma triglyceride clearance in man",

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.",

keywords = "APOLIPOPROTEIN-C-III, 2-DIMENSIONAL GEL-ELECTROPHORESIS, ANGIOPOIETIN-LIKE PROTEIN-3, LIPOPROTEIN-LIPASE S447X, RICH LIPOPROTEINS, MASS-SPECTROMETRY, HEPATIC-UPTAKE, GLYCOSYLATION, METABOLISM, APOPROTEINS",

author = "Holleboom, {Adriaan G.} and Helen Karlsson and Ruei-Shiuan Lin and Beres, {Thomas M.} and Sierts, {Jeroen A.} and Herman, {Daniel S.} and Stroes, {Erik S. G.} and Aerts, {Johannes M.} and Kastelein, {John J. P.} and Motazacker, {Mohammad M.} and Dallinga-Thie, {Geesje M.} and Levels, {Johannes H. M.} and Zwinderman, {Aeilko H.} and Seidman, {Jonathan G.} and Seidman, {Christine E.} and Stefan Ljunggren and Lefeber, {Dirk J.} and Eva Morava and Wevers, {Ron A.} and Fritz, {Timothy A.} and Tabak, {Lawrence A.} and Mats Lindahl and Hovingh, {G. Kees} and Kuivenhoven, {Jan Albert}",

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month = dec,

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doi = "10.1016/j.cmet.2011.11.005",

language = "English",

volume = "14",

pages = "811--818",

journal = "Cell metabolism",

issn = "1550-4131",

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Holleboom, AG, Karlsson, H, Lin, R-S, Beres, TM, Sierts, JA, Herman, DS, Stroes, ESG, Aerts, JM, Kastelein, JJP, Motazacker, MM, Dallinga-Thie, GM, Levels, JHM, Zwinderman, AH, Seidman, JG, Seidman, CE, Ljunggren, S, Lefeber, DJ, Morava, E, Wevers, RA, Fritz, TA, Tabak, LA, Lindahl, M, Hovingh, GK & Kuivenhoven, JA 2011, 'Heterozygosity for a loss-of-function mutation in GALNT2 improves plasma triglyceride clearance in man', Cell metabolism, vol. 14, no. 6, pp. 811-818. https://doi.org/10.1016/j.cmet.2011.11.005

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

In: Cell metabolism, Vol. 14, No. 6, 07.12.2011, p. 811-818.

Research output: Contribution to journal › Article › Academic › peer-review

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 - 2011/12/7

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.

KW - APOLIPOPROTEIN-C-III

KW - 2-DIMENSIONAL GEL-ELECTROPHORESIS

KW - ANGIOPOIETIN-LIKE PROTEIN-3

KW - LIPOPROTEIN-LIPASE S447X

KW - RICH LIPOPROTEINS

KW - MASS-SPECTROMETRY

KW - HEPATIC-UPTAKE

KW - GLYCOSYLATION

KW - METABOLISM

KW - APOPROTEINS

U2 - 10.1016/j.cmet.2011.11.005

DO - 10.1016/j.cmet.2011.11.005

M3 - Article

C2 - 22152306

VL - 14

SP - 811

EP - 818

JO - Cell metabolism

JF - Cell metabolism

SN - 1550-4131

IS - 6

ER -