Journal Articles

Pharmacological inhibition of NOX4 ameliorates alcohol-induced liver injury in mice through improving oxidative stress and mitochondrial function

September 22, 2016

Qian Suna, Wenliang Zhang, Wei Zhong, Xinguo Sun, Zhanxiang Zhou (2016). Pharmacological inhibition of NOX4 ameliorates alcohol-induced liver injury in mice through improving oxidative stress and mitochondrial function. Biochemica et Biophysica General Subjects.

Author Affiliations

Department of Nutrition, University of North Carolina at Greensboro, North Carolina Research Campus, Kannapolis, NC, USA 28081
Center for Translational Biomedical Research, University of North Carolina at Greensboro, North Carolina Research Campus, Kannapolis, NC, USA 28081

Abstract

Oxidative stress plays a crucial role in the development of alcoholic liver disease (ALD), however effective pharmacological treatments for oxidative injury is still lacking. The objective of this study was to determine whether inhibition of NADPH oxidase activity could reverse alcohol-induced liver injury via protecting mitochondrial functions. Methods: C57BL/6 J mice were pair-fed with Lieber-DeCarli control or ethanol diet for four week with or without administration with 30 mg/kg/d GKT137831, a NOX4 inhibitor for the last two weeks. H4IIEC3 cells were transfected with scrambled or NOX4 shRNA. Cells were then treated with 200 mM ethanol for 48 h. Results: Alcohol exposure induced NOX4 expression in the liver and mitochondrial fraction. GKT137831 partially reversed alcohol-induced liver injury and elevation of serum H2O2. The levels of mitochondrial ROS, mitochondrial DNA, respiratory chain complex IV, and hepatic ATP were partially reversed by GKT137831 after alcohol exposure. Furthermore GKT137831 ameliorated alcohol-induced lipid accumulation and increased HNF-4α and β-oxidation enzymes. GKT137831 also decreased alcohol-induced apoptosis coupled with decreased insertion of Bax into mitochondria and decreased activation of cleaved caspase-9 and cleaved PARP. Mechanistic study shows that ethanol induced expression of NOX4 in H4IIEC3 cells. Knockdown of NOX4 caused an increased mitochondrial membrane potential, decreased mitochondrial superoxide levels, reduced number of apoptotic cells, decreased lipid accumulation, and improved ATP levels and NAD +/NADH ratio after ethanol treatment. Conclusion: Pharmacological inhibition of NOX4 activity protects against alcohol-induced fat accumulation and activation of intrinsic apoptosis via improving mitochondrial function. General significance: Pharmacological inhibition of NOX4 could be a promising treatment for ALD.

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