Oxidative stress is a common feature observed in a wide spectrum of chronic liver diseases including viral hepatitis, alcoholic, and nonalcoholic steatohepatitis. The nicotinamide adenine dinucleotide phosphate (NADPH) oxidases (NOXs) are emerging as major sources of reactive oxygen species (ROS). Several major isoforms are expressed in the liver, including NOX1, NOX2, and NOX4. While the phagocytic NOX2 has been known to play an important role in Kupffer cell and neutrophil phagocytic activity and inflammation, the nonphagocytic NOX homologues are increasingly recognized as key enzymes in oxidative injury and wound healing. In this review, we will summarize the current advances in knowledge on the regulatory pathways of NOX activation, their cellular distribution, and their role in the modulation of redox signaling in liver diseases. 1. Introduction In chronic liver diseases, hepatocyte injury triggers Kupffer cell activation and hepatic stellate cell (HSC) transdifferentiation to matrix-producing myofibroblasts, and the accumulation of extracellular matrix leads to fibrosis and cirrhosis [1, 2]. Most if not all pathogenic insults in the liver can cause oxidative stress, inducing lipid peroxidation, protein oxidation, and DNA damage, leading to hepatocyte mitochondrial dysfunction, amplifying inflammation and initiating fibrosis [3]. As important second messengers, ROS can have an impact on cell death/survival pathways [4]. In the liver there are several important sources of ROS production. While the role of cytochrome P4502E1 (CYP2E1), the mitochondrial respiratory chain, arachidonic acid oxidation, and the xanthine oxidase system have been extensively studied in the past [5–7], recently the group of NOX enzymes have been emerging as major sources of ROS production. H2O2 is one of the main oxidative radicals during liver diseases and it is generated by the NADPH oxidases or complex III of the mitochondrial respiratory chain. In physiological situations the amount of H2O2 is under a tight control by the peroxiredoxins and glutathione peroxidases as well as by catalase [8]. During chronic liver injury however this balance is perturbed and parenchymal cells are exposed to increasing concentrations of ROS. Among the seven NOX homologues found in mammals (NOX1, NOX2, NOX3, NOX4, NOX5, DUOX1, and DUOX2), the main ROS-producing NOXs in the liver are NOX1, NOX2, and NOX4 [9] (Table 1). NOX1 and 2 are mainly producing superoxide whereas NOX4 directly produces H2O2. To form active complexes, NOX1 and NOX2 bind with their structural subunits: NOX1 associates
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