Oxidative stress is a potent link between hepatocyte damage and HSC activation in hepatic fibrosis

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Oxidative stress has a causative role in the development of hepatic fibrosis, or the deposition of extracellular matrix (ECM). Hepatic stellate cells (HSCs) functions as the production of ECM components in the injured liver. In addition, NF-κB is a key transcription factor that induces multiple genes in response to inflammation, infections, and oxidative stress. Signals that induce NF-κB activity cause the dissociation and subsequent degradation of IκB-α protein. Whereas many cells have their own unique enzymatic defense systems against oxidative stress, including the production of superoxide dismutase (SOD) and glutathione peroxidase (GPx), which play a critical role in protecting the cell from oxygen-derived free radicals and other reactive oxygen species. In this study, the fibrotic livers of the DMN model showed the increased hepatic levels of collagen and malondialdehyde (MDA), a product of lipid peroxidation, and reduced hepatic levels of SOD and GPx In addition, our study demonstrated that cultured rat hepatocytes respond robustly to oxidative stress with a time-dependent increase in degradation of IκB-α and subsequent NF-κB activation as well as in secretion of MDA and LDH into the culture medium. HSCs were found to be activated NF-κB along with the IκB-α degradation and be increased α-SMA expression and collagen production by MDA supplementation. These findings suggest that paracrine stimuli derived from hepatocytes undergoing oxidative stress induce HSC activation, at least in part, through the degradation of IκB-α and subsequent NF-κB activation.