α-Ketoglutaric acid ameliorates hyperglycemia in diabetes by inhibiting hepatic gluconeogenesis via serpina1e signaling

作者：Yuan, Yexian; Zhu, Canjun; Wang, Yongliang; Sun, Jia; Feng, Jinlong; Ma, Zewei; Li, Penglin; Peng, Wentong; Yin, Cong; Xu, Guli; Xu, Pingwen; Jiang, Yuwei; Jiang, Qingyan^*; Shu, Gang^*

来源：Science Advances, 2022, 8(18): eabn2879.

DOI：10.1126/sciadv.abn2879

• GLYCOGEN-SYNTHESIS
• RNA METHYLATION
• EXPRESSION
• AUTOPHAGY
• METABOLISM
• RECEPTORS
• PROMOTER
• MICE

Previously, we found that alpha-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.

• 单位
  华南农业大学; 西北农林科技大学; 南方医科大学