4.8 Article

Heterozygosity for a Loss-of-Function Mutation in GALNT2 Improves Plasma Triglyceride Clearance in Man

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CELL METABOLISM
卷 14, 期 6, 页码 811-818

出版社

CELL PRESS
DOI: 10.1016/j.cmet.2011.11.005

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资金

  1. European Union [FP6-2005-LIFESCIHEALTH-6, 037631]
  2. Fondation Leducq Transatlantic Networks of Excellence
  3. NWO [40-00506-98-9001]
  4. National Institute of Dental and Craniofacial Research (NIDCR), National Institutes of Health
  5. Netherlands Organisation for Scientific Research [021.001.035]
  6. Netherlands Heart Foundation [2010T082]

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Genome-wide association studies have identified GALNT2 as a candidate gene in lipid metabolism, but it is not known how the encoded enzyme ppGal-NAc-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 ppGaINAc-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 ppGaINAc-T2 can affect lipid metabolism through apoC-III glyco-sylation, thereby establishing GALNT2 as a lipid-modifying gene.

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