Abstract
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.
Highlights
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]
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 [5,6,7], recently the group of NOX enzymes have been emerging as major sources of reactive oxygen species (ROS) production
Macrophage activation Stellate cell activation Hepatocyte apoptosis Hepatic immune deregulation nuclear factor erythroid 2-related factor 2 (Nrf2) is a master regulator inducing the transcription of a spectrum of genes related to GSH metabolism via the antioxidant responsive element (ARE) on the target genes and is playing a role in xenobiotic detoxification and proteome maintenance [15]
Summary
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]. To maintain homeostasis free radicals are scavenged by a powerful antioxidant system in the liver composed of enzymatic and nonenzymatic molecules The former group consists of superoxide dismutases (SOD), catalase, and enzymes regulating glutathione (GSH) synthesis. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a master regulator inducing the transcription of a spectrum of genes related to GSH metabolism via the antioxidant responsive element (ARE) on the target genes and is playing a role in xenobiotic detoxification and proteome maintenance [15] Another group of transcription factors the Forkhead box O (FOXO) regulate the SOD and catalase transcripts [16, 17]. After prolonged chronic injury, the antioxidant responses gradually fail leading to the unopposed actions of ROS inflammation and fibrogenesis
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