Hepatic aberrant glycosylation by N-acetylglucosaminyltransferase V accelerates HDL assembly.
Hepatic aberrant glycosylation by N-acetylglucosaminyltransferase V accelerates HDL assembly.
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DOI：
10.1152/ajpgi.00231.2016
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发表时间：
2016-11
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通讯作者：
Y. Kamada;Sachiho Kida;K. Hirano;Satoshi Yamaguchi;A. Suzuki;Chikako Hashimoto;A. Kimura;M. Sato;Hironobu Fujii;Tomoaki Sobajima;Akiko Yamamoto;Yusuke Ebisutani;S. Takamatsu;S. Shinzaki;Y. Yoshida;Makoto Yamada;H. Nagasaka;T. Takehara;E. Miyoshi
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作者：
Y. Kamada;Sachiho Kida;K. Hirano;Satoshi Yamaguchi;A. Suzuki;Chikako Hashimoto;A. Kimura;M. Sato;Hironobu Fujii;Tomoaki Sobajima;Akiko Yamamoto;Yusuke Ebisutani;S. Takamatsu;S. Shinzaki;Y. Yoshida;Makoto Yamada;H. Nagasaka;T. Takehara;E. Miyoshi
糖基化参与各种病理生理学状况。N-乙酰葡糖胺转移酶V（GnT-V）催化天冬酰胺连接的寡糖中的β1-6分支，是参与癌症和免疫系统的最重要的糖基转移酶之一。最近的研究表明，异常的N-聚糖结构可以改变脂质代谢。在这项研究中，我们研究了异常糖基化GnT-V对高密度脂蛋白胆固醇（HDL）组装的影响。我们使用GnT-V转基因（Tg）小鼠和GnT-V Hep 3B细胞（人肝癌细胞系）转染子。该研究还包括96名接受医疗健康检查的患者。与野生型（WT）小鼠相比，Tg小鼠的血清总胆固醇水平，特别是HDL-胆固醇（HDL-C）水平显著升高。与WT小鼠相比，Tg小鼠的载脂蛋白AI（ApoAI）和ATP结合盒亚家族A成员1（ABCA 1）的肝脏表达更高，这是HDL组装中的两个重要因素。ApoAI和ABCA 1也显着升高GnT-V转染细胞相比，模拟转染细胞。此外，GnT-V转染细胞培养液中的ApoAI蛋白显著增加。最后，我们发现了人类受试者血清GnT-V活性和HDL-C浓度之间的强相关性。多因素Logistic分析表明，GnT-V活性是血清HDL-C水平的独立和重要的决定因素，即使调整了年龄和性别差异。进一步的分析表明，血清GnT-V活性有很强的相关性，特别是与大尺寸HDL颗粒浓度。这些发现表明肝脏GnT-V活性增强加速了HDL组装，并且可能是HDL合成的一种新机制。
Glycosylation is involved in various pathophysiological conditions. N-Acetylglucosaminyltransferase V (GnT-V), catalyzing β1-6 branching in asparagine-linked oligosaccharides, is one of the most important glycosyltransferases involved in cancer and the immune system. Recent findings indicate that aberrant N-glycan structure can modify lipid metabolism. In this study, we investigated the effects of aberrant glycosylation by GnT-V on high-density lipoprotein cholesterol (HDL) assembly. We used GnT-V transgenic (Tg) mice and GnT-V Hep3B cell (human hepatoma cell line) transfectants. The study also included 96 patients who underwent medical health check-ups. Total serum cholesterol levels, particularly HDL-cholesterol (HDL-C) levels, were significantly increased in Tg vs. wild-type (WT) mice. Hepatic expression of apolipoprotein AI (ApoAI) and ATP-binding cassette subfamily A member 1 (ABCA1), two important factors in HDL assembly, were higher in Tg mice compared with WT mice. ApoAI and ABCA1 were also significantly elevated in GnT-V transfectants compared with mock-transfected cells. Moreover, ApoAI protein in the cultured media of GnT-V transfectants was significantly increased. Finally, we found a strong correlation between serum GnT-V activity and HDL-C concentration in human subjects. Multivariate logistic analyses demonstrated that GnT-V activity was an independent and significant determinant for serum HDL-C levels even adjusted with age and gender differences. Further analyses represented that serum GnT-V activity had strong correlation especially with the large-size HDL particle concentration. These findings indicate that enhanced hepatic GnT-V activity accelerated HDL assembly and could be a novel mechanism for HDL synthesis.