GFAT2 mediates cardiac hypertrophy through HBP-O-GlcNAcylation-Akt pathway
GFAT2 mediates cardiac hypertrophy through HBP-O-GlcNAcylation-Akt pathway
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DOI：
10.1016/j.isci.2021.103517
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发表时间：
2021-12-17
期刊：
影响因子：
5.8
通讯作者：
Tsutsui, Hiroyuki
中科院分区：
文献类型：
--
作者：
Ishikita, Akihito;Matsushima, Shouji;Tsutsui, Hiroyuki
葡萄糖代谢介导心肌肥大的分子机制尚不完全清楚。己糖胺生物合成途径（HBP）是糖酵解的一条辅助途径，参与蛋白质的O-连接N-乙酰葡萄糖胺基序（O-GlcNAc化），是一种翻译后修饰。我们在这里证明，谷氨酰胺-果糖-6-磷酸酰胺转移酶2（GFAT 2），一个关键的HBP酶，是一个主要的异构体GFAT在心脏和增加响应几个肥大刺激，包括异丙肾上腺素（ISO）。GFAT 2的敲低可抑制ISO诱导的心肌细胞肥大，并伴有Akt O-GlcNAcylation和激活的抑制。GFAT 2的敲低不影响Akt抑制的抗肥大作用。葡糖胺（HBP的底物）的给药诱导蛋白O-GlcNAc酰化、Akt活化和心肌细胞肥大。在小鼠中，GFAT抑制剂6-重氮-5-氧代-L-正亮氨酸可减弱ISO诱导的蛋白O-GlcNAc酰化、Akt活化和心脏肥大。我们的研究结果表明，GFAT 2介导的心肌细胞肥大的HBP-O-GlcNAcylation-Akt途径，并可能是一个关键的治疗目标的心肌肥大。
Molecular mechanisms mediating cardiac hypertrophy by glucose metabolism are incompletely understood. Hexosamine biosynthesis pathway (HBP), an accessory pathway of glycolysis, is known to be involved in the attachment of O-linked N-acetylglucosamine motif (O-GlcNAcylation) to proteins, a post-translational modification. We here demonstrate that glutamine-fructose-6-phosphate amidotransferase 2 (GFAT2), a critical HBP enzyme, is a major isoform of GFAT in the heart and is increased in response to several hypertrophic stimuli, including isoproterenol (ISO). Knockdown of GFAT2 suppresses ISO-induced cardiomyocyte hypertrophy, accompanied by suppression of Akt O-GlcNAcylation and activation. Knockdown of GFAT2 does not affect anti-hypertrophic effect by Akt inhibition. Administration of glucosamine, a substrate of HBP, induces protein O-GlcNAcylation, Akt activation, and cardiomyocyte hypertrophy. In mice, 6-diazo-5-oxo-L-norleucine, an inhibitor of GFAT, attenuates ISO-induced protein O-GlcNAcylation, Akt activation, and cardiac hypertrophy. Our results demonstrate that GFAT2 mediates cardiomyocyte hypertrophy by HBP-O-GlcNAcylation-Akt pathway and could be a critical therapeutic target of cardiac hypertrophy.