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 journalArticleAcademicpeer-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 languageEnglish
Pages (from-to)811-818
Number of pages8
JournalCell metabolism
Volume14
Issue number6
DOIs
Publication statusPublished - 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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