Acute regulation of cardiac metabolism by the hexosamine biosynthesis pathway and protein O-GlcNAcylation.
Acute regulation of cardiac metabolism by the hexosamine biosynthesis pathway and protein O-GlcNAcylation.
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DOI：
10.1371/journal.pone.0018417
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发表时间：
2011-04-11
期刊：
影响因子：
3.7
通讯作者：
Chatham JC
中科院分区：
文献类型：
--
作者：
Laczy B;Fülöp N;Onay-Besikci A;Des Rosiers C;Chatham JC
己糖胺生物合成途径（HBP）通量和蛋白质O-连接的N-乙酰基-葡糖胺（O-GlcNAc）水平已经涉及介导糖尿病在心血管系统中的不利影响。已显示用葡糖胺激活这些途径可模拟糖尿病诱导的心脏功能和结构变化;然而，对心脏代谢的影响尚不清楚。因此，本研究的主要目的是确定氨基葡萄糖对心脏底物利用的影响。在常氧条件下，用葡糖胺（0-10 mM）灌注离体大鼠心脏以增加HBP通量。通过13 C-NMR同位素分析确定代谢通量;通过HPLC评估O-GlcNAc合成的前体UDP-GlcNAc，并使用免疫印迹分析确定O-GlcNAc水平、AMPK和ACC的磷酸化和总水平以及FAT/CD 36的膜水平。氨基葡萄糖导致UDP-GlcNAc和O-GlcNAc水平呈剂量依赖性增加，这与棕榈酸氧化显著增加以及乳酸和丙酮酸氧化伴随减少相关。葡萄糖胺对AMPK或ACC磷酸化没有影响;然而，脂肪酸转运蛋白FAT/CD 36的膜水平增加，初步研究表明FAT/CD 36是O-GlcNAc酰化的潜在靶点。这些数据表明，心脏中HBP和蛋白质O-GlcNAc化的急性调节可能通过增加FAT/CD 36的质膜水平刺激脂肪酸氧化，提高了HBP和O-GlcNAc周转代表用于调节心脏代谢的新型葡萄糖依赖性机制的有趣可能性。
The hexosamine biosynthesis pathway (HBP) flux and protein O-linked N-acetyl-glucosamine (O-GlcNAc) levels have been implicated in mediating the adverse effects of diabetes in the cardiovascular system. Activation of these pathways with glucosamine has been shown to mimic some of the diabetes-induced functional and structural changes in the heart; however, the effect on cardiac metabolism is not known. Therefore, the primary goal of this study was to determine the effects of glucosamine on cardiac substrate utilization. Isolated rat hearts were perfused with glucosamine (0–10 mM) to increase HBP flux under normoxic conditions. Metabolic fluxes were determined by 13C-NMR isotopomer analysis; UDP-GlcNAc a precursor of O-GlcNAc synthesis was assessed by HPLC and immunoblot analysis was used to determine O-GlcNAc levels, phospho- and total levels of AMPK and ACC, and membrane levels of FAT/CD36. Glucosamine caused a dose dependent increase in both UDP-GlcNAc and O-GlcNAc levels, which was associated with a significant increase in palmitate oxidation with a concomitant decrease in lactate and pyruvate oxidation. There was no effect of glucosamine on AMPK or ACC phosphorylation; however, membrane levels of the fatty acid transport protein FAT/CD36 were increased and preliminary studies suggest that FAT/CD36 is a potential target for O-GlcNAcylation. These data demonstrate that acute modulation of HBP and protein O-GlcNAcylation in the heart stimulates fatty acid oxidation, possibly by increasing plasma membrane levels of FAT/CD36, raising the intriguing possibility that the HBP and O-GlcNAc turnover represent a novel, glucose dependent mechanism for regulating cardiac metabolism.
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影响因子：
5.5
作者：
Champattanachai, Voraratt;Marchase, Richard B.;Chatham, John C.
通讯作者：
Chatham, John C.
影响因子：
4.3
作者：
Coort, Susan L. M.;Bonen, Arend;van der Vusse, Ger J.;Glatz, Jan F. C.;Luiken, Joost J. F. P.
通讯作者：
Luiken, Joost J. F. P.
影响因子：
37.8
作者：
Kuang, M;Febbraio, M;Dyck, JRB
通讯作者：
Dyck, JRB
DOI：
10.1152/ajpendo.1999.277.2.e342
发表时间：
1999-08-01
影响因子：
5.1
作者：
Chatham, JC;Gao, ZP;Forder, JR
通讯作者：
Forder, JR
DOI：
10.1152/ajpheart.01091.2006
发表时间：
2007-05-01
影响因子：
4.8
作者：
Fulop, Norbert;Zhang, Zhenghao;Chatham, John C.
通讯作者：
Chatham, John C.