Bao Kehan, Berger Jason, Na Erqian, Su Qi, Halasz Gabor, Sleeman Mark, Okamoto Haruka
Regeneron Pharmaceuticals, Tarrytown, NY.
Diabetes. 2025 Jun 1;74(6):885-897. doi: 10.2337/db24-0958.
Glucagon stimulates hepatic glucose production, in part by promoting the uptake and catabolism of amino acids. Inhibition of the liver glucagon receptor (GCGR) results in elevated plasma amino acids, which triggers the proliferation of pancreatic α-cells, forming a liver-α-cell loop. This study aims to delineate hepatic signaling molecules downstream of GCGR that mediate the liver-α-cell loop. We knocked down liver GCGR, its G-coupled protein GNAS, and two GNAS downstream effectors, PKA and EPAC2 (RAPGEF4). Mice with GCGR, GNAS, and PKA knockdown had similar suppression of hepatic amino acid catabolism genes, hyperaminoacidemia, and α-cell hyperplasia, but those with EPAC2 knockdown did not. We then demonstrated that activating liver PKA was sufficient to reverse hyperaminoacidemia and α-cell hyperplasia caused by GCGR blockade. These results suggest that liver GCGR signals through PKA to control amino acid metabolism and that hepatic PKA plays a critical role in the liver-α-cell loop.
A liver-α-cell loop exists, where inhibition of the liver glucagon receptor (GCGR) causes hyperaminoacidemia and pancreatic α-cell hyperplasia, but the GCGR downstream factors responsible for these effects are not clear. We silenced GCGR, its G-coupled protein GNAS, and two GNAS downstream effectors, PKA and EPAC2, to assess their effects on the liver-α-cell loop. Inhibition of the GCGR-GNAS-PKA pathway suppresses amino acid catabolism and causes α-cell hyperplasia, whereas PKA activation promotes amino acid catabolism and reduces alpha cell mass even when GCGR is blocked. Our study establishes hepatic PKA as the critical regulator of the liver-α-cell loop.
胰高血糖素刺激肝脏葡萄糖生成，部分原因是促进氨基酸的摄取和分解代谢。抑制肝脏胰高血糖素受体（GCGR）会导致血浆氨基酸水平升高，从而触发胰腺α细胞增殖，形成肝脏-α细胞环路。本研究旨在阐明GCGR下游介导肝脏-α细胞环路的信号分子。我们敲低了肝脏GCGR、其G偶联蛋白GNAS以及两个GNAS下游效应物PKA和EPAC2（RAPGEF4）。敲低GCGR、GNAS和PKA的小鼠对肝脏氨基酸分解代谢基因的抑制作用、高氨基酸血症和α细胞增生情况相似，但敲低EPAC2的小鼠则不然。然后我们证明激活肝脏PKA足以逆转由GCGR阻断引起的高氨基酸血症和α细胞增生。这些结果表明肝脏GCGR通过PKA发出信号来控制氨基酸代谢，并且肝脏PKA在肝脏-α细胞环路中起关键作用。
存在肝脏-α细胞环路，其中抑制肝脏胰高血糖素受体（GCGR）会导致高氨基酸血症和胰腺α细胞增生，但负责这些效应的GCGR下游因子尚不清楚。我们使GCGR、其G偶联蛋白GNAS以及两个GNAS下游效应物PKA和EPAC2沉默，以评估它们对肝脏-α细胞环路的影响。抑制GCGR-GNAS-PKA途径会抑制氨基酸分解代谢并导致α细胞增生，而PKA激活即使在GCGR被阻断时也能促进氨基酸分解代谢并减少α细胞数量。我们的研究确定肝脏PKA是肝脏-α细胞环路的关键调节因子。
