Aquaporin 8 is involved in H2O2-mediated differential regulation of metabolic signaling by α1- and β-adrenoceptors in hepatocytes

Abstract

Reactive oxygen species participate in regulating intracellular signaling pathways. Herein, we investigated the reported opposite effects of hydrogen peroxide (H2O2) on metabolic signaling mediated by activated α1- and β-adrenoceptors (ARs) in hepatocytes. In isolated rat hepatocytes, stimulation of α1-AR increases H2O2 production via NADPH oxidase 2 (NOX2) activation. We find that the H2O2 thus produced is essential for α1-AR-mediated activation of the classical hepatic glycogenolytic, gluconeogenic, and ureagenic responses. However, H2O2 inhibits β-AR-mediated activation of these metabolic responses. We show that H2O2 mediates its effects on α1-AR and β-AR by permeating cells through aquaporin 8 (AQP8) channels and promoting Ca2+ mobilization. Thus, our findings reveal a novel NOX2-H2O2-AQP8-Ca2+ signaling cascade acting downstream of α1-AR in hepatocytes, which, by negatively regulating β-AR signaling, establishes negative crosstalk between the two pathways.