Hepatic PKA Mediates Liver and Pancreatic α-Cell Cross Talk

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.