| First Author | Yuan Y | Year | 2022 |
| Journal | Sci Adv | Volume | 8 |
| Issue | 18 | Pages | eabn2879 |
| PubMed ID | 35507647 | Mgi Jnum | J:327478 |
| Mgi Id | MGI:7278220 | Doi | 10.1126/sciadv.abn2879 |
| Citation | Yuan Y, et al. (2022) alpha-Ketoglutaric acid ameliorates hyperglycemia in diabetes by inhibiting hepatic gluconeogenesis via serpina1e signaling. Sci Adv 8(18):eabn2879 |
| abstractText | 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. |
