Hepatic PKA Mediates the Liver and Pancreatic Alpha-Cell Crosstalk

Abstract

Glucagon stimulates hepatic glucose production, in part by promoting the uptake and catabolism of amino acids. Inhibition of liver glucagon receptor (GCGR) results in elevated plasma amino acids, which triggers the proliferation of pancreatic alpha-cells, forming a liver-alpha cell loop. This study aims to delineate hepatic signaling molecules downstream of GCGR which mediate the liver-alpha 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 alpha cell hyperplasia, but EPAC2 knockdown did not. We then demonstrated that activating liver PKA was sufficient to reverse hyperaminoacidemia and alpha 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-alpha cell loop.