Aquaporin 8 is involved in H O -mediated differential regulation of metabolic signaling by α - and β-adrenoceptors in hepatocytes.

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