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.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project (R01)
Project #
5R01AA017738-05
Application #
8319659
Study Section
Special Emphasis Panel (ZAA1-JJ (17))
Program Officer
Murray, Gary
Project Start
2008-09-30
Project End
2014-08-31
Budget Start
2012-09-01
Budget End
2014-08-31
Support Year
5
Fiscal Year
2012
Total Cost
$317,949
Indirect Cost
$103,842
Name
University of Nebraska Medical Center
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
168559177
City
Omaha
State
NE
Country
United States
Zip Code
68198
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
Harrison-Findik, Duygu Dee (2009) Is the iron regulatory hormone hepcidin a risk factor for alcoholic liver disease? World J Gastroenterol 15:1186-93
Harrison-Findik, Duygu Dee; Klein, Elizabeth; Evans, John et al. (2009) Regulation of liver hepcidin expression by alcohol in vivo does not involve Kupffer cell activation or TNF-alpha signaling. Am J Physiol Gastrointest Liver Physiol 296:G112-8