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 (H 2 O 2 ) on metabolic signaling mediated by activated a 1 -and b-adrenoceptors (ARs) in hepatocytes. In isolated rat hepatocytes, stimulation of a 1 -AR increases H 2 O 2 production via NADPH oxidase 2 (NOX2) activation. We find that the H 2 O 2 thus produced is essential for a 1 -AR-mediated activation of the classical hepatic glycogenolytic, gluconeogenic, and ureagenic responses. However, H 2 O 2 inhibits b-AR-mediated activation of these metabolic responses. We show that H 2 O 2 mediates its effects on a 1 -AR and b-AR by permeating cells through aquaporin 8 (AQP8) channels and promoting Ca 2+ mobilization. Thus, our findings reveal a novel NOX2-H 2 O 2 -AQP8-Ca 2+ signaling cascade acting downstream of a 1 -AR in hepatocytes, which, by negatively regulating b-AR signaling, establishes negative crosstalk between the two pathways.

The impact of chronic stress on intracellular redox balance: A systems level analysis

“…Moreover, the redox changes observed in the prefrontal cortex region were not reflected in the hippocampus or the cerebellum. The Western blotting data suggest that such an increase in SOD activity is likely due to post‐translational modifications and not due to increased expression levels (Bouayed & Soulimani, 2019 ; Díaz‐Cruz et al, 2007 , 2011 ; Fisher, 2009 ; Maher & Schubert, 2000 ; Vilchis‐Landeros et al, 2020 ; Wang et al, 2018 ). This could suggest an adaptive mechanism at play in the prefrontal cortex in response to increased signaling demands.…”

Regulation of Metabolic Processes by Hydrogen Peroxide Generated by NADPH Oxidases

“…Negative cross-talk between α 1 -ARs and β-ARs for H 2 O 2 synthesis, gluconeogenesis, and ureagenesis was observed in these cells [83,84]. AQP8 is necessary for H 2 O 2 to enter the hepatocyte and carry out its function [85]. Based on previous work [88], H 2 O 2 generated after NOX2 activation by α 1 -AR in hepatocytes may react with cAMP-dependent protein kinase A (PKA) and inhibit gluconeogenesis and ureagenesis processes (Figure 2).…”

“…Hepatocytes contain many ROS-generating systems, including cytochromes, mitochondrial respiration, arachidonic acid oxidation, and NOXs. The generation of ROS through an NOX has been described in response to many stimuli like adrenaline [83][84][85], CD95 ligand [78], TGF-β [86], and bile production in hepatocytes [87]. Adrenaline activates the NOX2 enzyme, localized in hepatocyte plasma membranes through the α 1 -adrenoreceptors (α 1 -AR).…”

Aquaporins in Glandular Secretion

“…Since H 2 O 2 inhibits the β-AR-mediated activation of the glycogenolytic, gluconeogenic, and ureagenic responses induced by α 1 -AR this observation was suggested to be a novel NOX2-H 2 O 2 -AQP8-Ca 2+ signaling cascade acting downstream of α 1 -AR in hepatocytes. The inhibitory effect exerted by H 2 O 2 on β-AR signaling leads to negative crosstalk between the two pathways [153]. Intense is the investigation addressed to the role exerted by AQP8 in the secretion of canalicular bile.…”