α-Ketoglutaric acid ameliorates hyperglycemia in diabetes by inhibiting hepatic gluconeogenesis via serpina1e signaling.
α-Ketoglutaric acid ameliorates hyperglycemia in diabetes by inhibiting hepatic gluconeogenesis via serpina1e signaling.
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DOI：
10.1126/sciadv.abn2879
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发表时间：
2022-05-06
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影响因子：
13.6
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中科院分区：
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先前，我们发现α-酮戊二酸通过2-氧-戊二酸受体1刺激肌肉肥大和脂肪减少。在这里，我们证明了AKG对饮食诱导肥胖(DIO)小鼠模型的葡萄糖稳态的有益影响，这种作用不依赖于OXGR1。我们还发现AKG能有效降低DIO小鼠的血糖和肝脏糖异生。通过建立转录型和肝特异性丝氨酸缺失的小鼠模型，我们进一步证明了AKG对肝脏糖异生的抑制作用需要肝脏丝氨酸。从机制上讲，我们支持细胞外AKG与嘌呤能受体P2RX4结合，启动细胞内AKG的溶质载体家族25成员11(SLC25A11)依赖的核转位，从而诱导组蛋白3(H3K27)上的赖氨酸27去甲基化，从而减少肝脏的糖异生。总之，这些发现揭示了一种利用循环AKG作为信号分子来控制肝脏糖异生的意想不到的机制。α-酮戊二酸通过血清信号途径抑制肝脏糖异生，从而改善糖尿病患者的高血糖。
Previously, we found that α-ketoglutaric acid (AKG) stimulates muscle hypertrophy and fat loss through 2-oxoglutarate receptor 1 (OXGR1). Here, we demonstrated the beneficial effects of AKG on glucose homeostasis in a diet-induced obesity (DIO) mouse model, which are independent of OXGR1. We also showed that AKG effectively decreased blood glucose and hepatic gluconeogenesis in DIO mice. By using transcriptomic and liver-specific serpina1e deletion mouse model, we further demonstrated that liver serpina1e is required for the inhibitory effects of AKG on hepatic gluconeogenesis. Mechanistically, we supported that extracellular AKG binds with a purinergic receptor, P2RX4, to initiate the solute carrier family 25 member 11 (SLC25A11)–dependent nucleus translocation of intracellular AKG and subsequently induces demethylation of lysine 27 on histone 3 (H3K27) in the seprina1e promoter region to decrease hepatic gluconeogenesis. Collectively, these findings reveal an unexpected mechanism for control of hepatic gluconeogenesis using circulating AKG as a signal molecule. α-Ketoglutaric acid ameliorates hyperglycemia in diabetes by inhibiting hepatic gluconeogenesis via serpina1e signaling.
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