Is the iron regulatory hormone hepcidin a risk factor for alcoholic liver disease?

Abstract

Despite heavy consumption over a long period of time, only a small number of alcoholics develop alcoholic liver disease. This alludes to the possibility that other factors, besides alcohol, may be involved in the progression of the disease. Over the years, many such factors have indeed been identified, including iron. Despite being crucial for various important biological processes, iron can also be harmful due to its ability to catalyze Fenton chemistry. Alcohol and iron have been shown to interact synergistically to cause liver injury. Iron-mediated cell signaling has been reported to be involved in the pathogenesis of experimental alcoholic liver disease. Hepcidin is an iron-regulatory hormone synthesized by the liver, which plays a pivotal role in iron homeostasis. Both acute and chronic alcohol exposure suppress hepcidin expression in the liver. The sera of patients with alcoholic liver disease, particularly those exhibiting higher serum iron indices, have also been reported to display reduced prohepcidin levels. Alcohol-mediated oxidative stress is involved in the inhibition of hepcidin promoter activity and transcription in the liver. This in turn leads to an increase in intestinal iron transport and liver iron storage. Hepcidin is expressed primarily in hepatocytes. It is noteworthy that both hepatocytes and Kupffer cells are involved in the progression of alcoholic liver disease. However, the activation of Kupffer cells and TNF-alpha signaling has been reported not to be involved in the down-regulation of hepcidin expression by alcohol in the liver. Alcohol acts within the parenchymal cells of the liver to suppress the synthesis of hepcidin. Due to its crucial role in the regulation of body iron stores, hepcidin may act as a secondary risk factor in the progression of alcoholic liver disease. The clarification of the mechanisms by which alcohol disrupts iron homeostasis will allow for further understanding of the pathogenesis of alcoholic liver disease.

Figure 1

The Iron regulatory hormone hepcidin. Hepcidin is synthesized in the hepatocytes of the liver as an 84 amino acid precursor protein. It is subsequently cleaved into the 25 amino acid biologically active peptide form and is released into the circulation. Hepcidin plays a central role in the regulation of iron metabolism by inhibiting the release of iron from the enterocytes of the duodenum and from reticuloendothelial macrophages. Hepcidin blocks the export of iron from these cells by binding to the iron exporter protein, ferroportin, which induces the internalization and degradation of ferroportin protein. As a soluble mediator, hepcidin establishes the cross-talk between distant organs in the body in order to maintain iron homeostasis.

Figure 2

Hepcidin and alcohol. Alcohol is metabolized by alcohol dehydrogenase (ADH) and cytochrome P4502E1 (CYP2E1) in the liver. Alcohol-induced oxidative stress leads to the suppression of hepcidin promoter activity and hepcidin transcription in the liver. The parenchymal, but not the non-parenchymal cells of the liver are involved in the regulation of hepcidin transcription by alcohol-induced oxidative stress. The activation of CYP2E1 or NADPH oxidase and changes in mitochondrial functions are involved in alcohol-induced oxidative stress in hepatocytes. The role of these pathways in the regulation of hepcidin transcription by alcohol requires further investigation.