Heterozygosity for a loss-of-function mutation in GALNT2 improves plasma triglyceride clearance in man.
Heterozygosity for a loss-of-function mutation in GALNT2 improves plasma triglyceride clearance in man.
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DOI：
10.1016/j.cmet.2011.11.005
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发表时间：
2011-12-07
期刊：
影响因子：
29
通讯作者：
Kuivenhoven JA
中科院分区：
文献类型：
--
作者：
Holleboom AG;Karlsson H;Lin RS;Beres TM;Sierts JA;Herman DS;Stroes ES;Aerts JM;Kastelein JJ;Motazacker MM;Dallinga-Thie GM;Levels JH;Zwinderman AH;Seidman JG;Seidman CE;Ljunggren S;Lefeber DJ;Morava E;Wevers RA;Fritz TA;Tabak LA;Lindahl M;Hovingh GK;Kuivenhoven JA
全基因组关联研究已经确定GALNT2是脂代谢的候选基因，但目前尚不清楚参与启动粘蛋白O连接糖基化的编码酶ppGal-NAC-T2是如何介导这一效应的。在两个血浆高密度脂蛋白胆固醇升高和甘油三酯降低的先证者中，我们发现了GALNT2的突变。研究表明，携带者改善了餐后甘油三酯的清除，这可能是由于他们血浆中观察到的载脂蛋白(Apo)C-III糖基化减弱所致。这种蛋白质抑制脂蛋白脂酶(LPL)，后者能分解血浆甘油三酯。我们发现，基于apoC-III的多肽是ppGalNAc-T2的底物，而突变酶对其糖基化作用是受损的。此外，神经氨酸酶处理apoC-III，它从其糖链上移除唾液酸，降低其抑制LPL的潜力。综上所述，这些数据表明ppGalNAc-T2可以通过apoC-III糖基化影响脂质代谢，从而确立GALNT2是一个脂质修饰基因。
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 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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与人类血液低密度脂蛋白胆固醇、高密度脂蛋白胆固醇或甘油三酯相关的六个新位点。
影响因子：
30.8
作者：
Kathiresan, Sekar;Melander, Olle;Guiducci, Candace;Surti, Aarti;Burtt, Noel P.;Rieder, Mark J.;Cooper, Gregory M.;Roos, Charlotta;Voight, Benjamin F.;Havulinna, Aki S.;Wahlstrand, Bjorn;Hedner, Thomas;Corella, Dolores;Tai, E. Shyong;Ordovas, Jose M.;Berglund, Goran;Vartiainen, Erkki;Jousilahti, Pekka;Hedblad, Bo;Taskinen, Marja-Riitta;Newton-Cheh, Christopher;Salomaa, Veikko;Peltonen, Leena;Groop, Leif;Altshuler, David M.;Orho-Melander, Marju
通讯作者：
Orho-Melander, Marju
影响因子：
4.8
作者：
Schjoldager, Katrine T. -B. G.;Vester-Christensen, Malene B.;Clausen, Henrik
通讯作者：
Clausen, Henrik
影响因子：
3.4
作者：
Karlsson, H;Leanderson, P;Lindahl, M
通讯作者：
Lindahl, M
影响因子：
2
作者：
Bruneel, Arnaud;Robert, Tiphaine;Seta, Nathalie
通讯作者：
Seta, Nathalie
影响因子：
48
作者：
Herman, Daniel S.;Hovingh, G. Kees;Seidman, Christine E.
通讯作者：
Seidman, Christine E.