Hepatic PKA Mediates Liver and Pancreatic α-Cell Cross Talk

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.