Mitochondria are critical in iron metabolism and play a role in alcohol-induced liver injury. Alcohol alters mitochondrial function and leads to oxidative stress. We have demonstrated that alcohol-induced oxidative stress down-regulates hepcidin transcription without causing changes in liver histology or an increase in triglycerides. Hepcidin is a circulatory peptide synthesized in the liver. It plays a central role in iron homeostasis by regulating both intestinal and reticulo-endothelial iron transport. Accordingly, alcohol-treated animals exhibited an increase in the expression of iron transporters in the duodenum and the iron storage protein, ferritin in the liver. Alcohol also rendered hepcidin synthesis in the liver insensitive to body iron levels. It is noteworthy, that hepcidin protects the body from iron overload by inhibiting iron transport. Thus, alcohol may compromise this protective mechanism of hepcidin, which may have implications for alcoholic liver disease (ALD). Of note, ALD patients and animal models of ALD display iron overload but the underlying mechanisms are unclear. Our findings suggest that the deregulation of hepcidin synthesis in the liver may be one of the underlying mechanisms of iron overload observed in ALD. Treatment with antioxidants abolished the effect of alcohol on hepcidin expression. Multiple pathways play a role in alcohol-induced oxidative stress, including activation of Kupffer cells, CYP2E1 enzyme and changes to mitochondrial function. Our preliminary results exclude a role for Kupffer cells, TNF alpha cytokine and CYP2E1 in the regulation of hepcidin expression by alcohol-mediated oxidative stress in the liver. Mitochondria also are involved in alcohol-mediated oxidative stress. Alcohol induces lesions in the proteins of the electron transport chain, and reduces ATP/ADP translocation and ATP synthesis in the mitochondria. Our preliminary results suggest a role for mitochondria in the regulation of hepcidin expression. Inhibition of DNA and protein synthesis in the mitochondria caused a significant decrease in hepcidin expression in plain HepG2 hepatoma cells. Mitochondria play a key role in apoptosis and alcohol-mediated changes in mitochondria induce apoptotic stimuli. However, the role of apoptosis in the regulation of hepcidin expression is unknown. Our preliminary findings demonstrate that Fas-mediated apoptosis down-regulates hepcidin expression in the liver. The objective of this application is to identify the molecular mechanisms whereby mitochondria regulate liver hepcidin expression and iron metabolism by alcohol. Our central hypothesis is that ethanol-induced modifications of mitochondrial structure and function play a key role in the regulation of hepcidin transcription by alcohol. We will employ transgenic mouse models deficient in mitochondrial antioxidant enzymes, adenine nucleotide transport, cytochrome c oxidase activity or the dimerization of hypoxia-inducible transcription factors to study the regulation of hepcidin transcription by alcohol-mediated oxidative stress. The knowledge obtained from these studies, characterizing the pivotal role of mitochondria, will enable us to determine the mechanisms of liver injury caused by iron and alcohol in patients with ALD.

National Institute of Health (NIH)
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
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Special Emphasis Panel (ZAA1-JJ (17))
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Murray, Gary
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University of Nebraska Medical Center
Internal Medicine/Medicine
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Lu, Sizhao; Bennett, Robert G; Kharbanda, Kusum K et al. (2016) Lack of hepcidin expression attenuates steatosis and causes fibrosis in the liver. World J Hepatol 8:211-25
Lu, Sizhao; Natarajan, Sathish Kumar; Mott, Justin L et al. (2016) Ceramide Induces Human Hepcidin Gene Transcription through JAK/STAT3 Pathway. PLoS One 11:e0147474
Lu, S; Seravalli, J; Harrison-Findik, D (2015) Inductively coupled mass spectrometry analysis of biometals in conditional Hamp1 and Hamp1 and Hamp2 transgenic mouse models. Transgenic Res 24:765-73
Harrison-Findik, Duygu Dee; Lu, Sizhao (2015) The effect of alcohol and hydrogen peroxide on liver hepcidin gene expression in mice lacking antioxidant enzymes, glutathione peroxidase-1 or catalase. Biomolecules 5:793-807
Lu, Sizhao; Mott, Justin L; Harrison-Findik, Duygu Dee (2015) Saturated fatty acids induce post-transcriptional regulation of HAMP mRNA via AU-rich element-binding protein, human antigen R (HuR). J Biol Chem 290:24178-89
Lu, Sizhao; Zmijewski, Emily; Gollan, John et al. (2014) Apoptosis induced by Fas signaling does not alter hepatic hepcidin expression. World J Biol Chem 5:387-97
Zmijewski, Emily; Lu, Sizhao; Harrison-Findik, Duygu Dee (2014) TLR4 signaling and the inhibition of liver hepcidin expression by alcohol. World J Gastroenterol 20:12161-70
Lu, Si-Zhao; Harrison-Findik, Duygu Dee (2013) Autophagy and cancer. World J Biol Chem 4:64-70
Harrison-Findik, Duygu Dee; Lu, Sizhao; Zmijewski, Emily M et al. (2013) Effect of alcohol exposure on hepatic superoxide generation and hepcidin expression. World J Biol Chem 4:119-30
Gerjevic, Lisa Nicole; Liu, Na; Lu, Sizhao et al. (2012) Alcohol Activates TGF-Beta but Inhibits BMP Receptor-Mediated Smad Signaling and Smad4 Binding to Hepcidin Promoter in the Liver. Int J Hepatol 2012:459278

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