Alcohol Metabolism-mediated Oxidative Stress Down-regulates Hepcidin Transcription and Leads to Increased Duodenal Iron Transporter Expression

Abstract

Patients with alcoholic liver disease frequently exhibit iron overload in association with increased hepatic fibrosis. Even moderate alcohol consumption elevates body iron stores; however, the underlying molecular mechanisms are unknown. Hepcidin, a circulatory peptide synthesized in the liver, is a key mediator of iron metabolism. Ethanol metabolism significantly down-regulated both in vitro and in vivo hepcidin mRNA and protein expression. 4-Methylpyrazole, a specific inhibitor of the alcohol-metabolizing enzymes, abolished the effects of ethanol on hepcidin. However, ethanol did not alter the expression of transferrin receptor1 and ferritin or the activation of iron regulatory RNA-binding proteins, IRP1 and IRP2. Mice maintained on 10 -20% ethanol for 7 days displayed down-regulation of liver hepcidin expression without changes in liver triglycerides or histology. This was accompanied by elevated duodenal divalent metal transporter1 and ferroportin protein expression. Injection of hepcidin peptide negated the effect of ethanol on duodenal iron transporters. Ethanol down-regulated hepcidin promoter activity and the DNA binding activity of CCAAT/enhancer-binding protein ␣ (C/EBP␣) but not ␤. Interestingly, the antioxidants vitamin E and N-acetylcysteine abolished both the alcohol-mediated down-regulation of C/EBP␣ binding activity and hepcidin expression in the liver and the up-regulation of duodenal divalent metal transporter 1. Collectively, these findings indicate that alcohol metabolism-mediated oxidative stress regulates hepcidin transcription via C/EBP␣, which in turn leads to increased duodenal iron transport.

Altered expression of iron regulatory genes in cirrhotic human livers: clues to the cause of hemosiderosis?

“…This issue may be resolved by examination of a larger number of bona fide normal human livers; however, such an undertaking will be difficult owing to ethical and logistic considerations. The concept linking downregulated hepcidin expression with hemosiderosis is supported by recent studies showing decreased hepatic hepcidin expression after short-term alcohol administration to mice 28 and with increasing age in HCV polyprotein transgenic mice. 29 Although these data establish that hepcidin expression can be modulated by alcohol and HCV, two important causes of chronic liver disease in humans, the relevance of these observations to patients with cirrhosis is uncertain.…”

“…On the one hand, there are no data to indicate that the alcohol-induced reduction in hepcidin expression results in hepatic iron accumulation, which would be unlikely in any case, given the brief (7 days) duration of the experiment. 28 Whether longer-term exposure to alcohol would result in persistent downregulation of hepcidin expression and/or dysregulation of iron metabolism is unknown at present, but it is worth noting that previous work in alcohol-treated rodents has failed to demonstrate spontaneous iron overload. 30,31 On the other hand, in contrast to HCV-infected humans, in whom hemosiderosis is uncommon before the development of advanced fibrosis, 32 HCV transgenic mice develop mild hepatic iron deposition in the absence of hepatic fibrosis.…”

Hemochromatosis: An endocrine liver disease

“…10,11 As for the contribution of nongenetic factors, ethanol abuse (long associated with iron overload) is now believed to inhibit hepcidin transcription. 12,13 Similar effects can be produced by toxic and viral insults (for example, the hepatitis C virus may inhibit hepcidin expression 14 ). The unexplained hepatic iron overload associated with acute liver failure and chronic end-stage liver disease, which closely resembles that of hemochromatosis, 15 may be a manifestation of diminished hepcidin output due to a markedly reduced functional hepatic mass.…”

Iron storage disease: Facts, fiction and progress

“…However, in some large studies there is a tendency for serum ferritin levels to be somewhat higher and liver function tests to be more abnormal in patients who ingest 60 g or more of alcohol when compared to homozygotes ingesting less alcohol [41] and in one study the incidence of cirrhosis was 9 times as high in such patients [42]. Hepcidin mRNA is decreased [43,44] and iron absorption is increased [43] by alcohol in normal 129x1/SvJ mice, but, somewhat surprisingly, the already elevated iron absorption in hfe knockout mice is not increased further by alcohol ingestion [43]. The effect of alcohol in mice is highly strain specific [43], and therefore caution must be exercised in extrapolating the murine findings to man.…”