This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.Increases in oxidative stress correspond to the severity of liver diseases such as alcoholic liver disease (ALD) and hepatitis C. Patients with ALD or chronic hepatitus C virus infection frequently display iron overload. Iron acts synergistically with other agents (i.e. alcohol, hepatitis C virus) causing lipid peroxidation and oxidative stress, leading to liver injury. However, the underlying mechanisms of iron accumulation are unclear. In the last decade, novel iron-regulatory proteins, including soluble mediators and iron transporters, have been discovered. Hepcidin is a circulatory peptide synthesized in the liver. Hepcidin plays a key role in the regulation of iron homeostasis by regulating iron transport in the intestine and macrophages. Recently, we have demonstrated that alcohol-induced oxidative stress down-regulates hepcidin expression in the liver, which leads to an increased intestinal expression of the iron transporter protein, ferroportin, in vivo. This process was inhibited by injecting mice with antioxidants. In addition, our findings demonstrate that the redox changes and oxidative stress associated with alcohol metabolism also inhibit hepacidin promoter activity, and the DNA-binding activity of C/EBP alpha, which is known to regulate hepcidin transcription. It is noteworthy that hepcidin synthesis in the liver responds to body iron levels, and is up-regulated by iron overload in vivo. However, we have demonstrated that alcohol renders liver hepcidin synthesis insensitive to body iron levels. Collectively, these findings suggest that the mechanisms which protect the body from the harmful effects of iron overload (eg. increased hepcidin expression and decreased iron transport) are compromised by alcohol-mediated oxidative stress. Interestingly, CD95 (Apo1/Fas) ligand-mediated apoptosis also down-regulates liver hepcidin expression, which is inhibited by antioxidants in vivo. Furthermore, our preliminary results demonstrate a role for NADPH oxidase enzyme in the regulation of hepcidin expression in vivo.
The aim of this project is to investigate the molecular mechanisms by which the redox signaling and plasma membrane-associated redox enzymes in the liver regulate the expression of iron-regulatory genes by alcohol and apoptosis in vivo. For these studies, we will employ mice, including NADPH oxidase knockout mice, as in vivo models, and primary mouse hepatocytes and human hepatoma cells as in vitro models. A better understanding of these mechanisms may help us to develop novel therapeutic strategies and diagnostic tools for liver diseases.
Showing the most recent 10 out of 177 publications
