Effects of Alcohol Consumption on Iron Metabolism in Mice with Hemochromatosis Mutations

Flanagan, Jonathan M.; Peng, Hongfan; Beutler, Ernest

doi:10.1111/j.1530-0277.2006.00275.x

Cited by 32 publications

(35 citation statements)

References 24 publications

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“…82,83 Mice of alcohol-susceptible strains that were also homozygous for a knockout of Hfe (orthologue of human HFE gene) had reduced iron absorption and serum hepcidin levels in response to alcohol treatment. 84 This finding indicates that either maximal suppression of hepcidin levels had already occurred as a result of the Hfe knockout or that Hfe protein was a component of the pathway used by ethanol in suppressing hepcidin production and increasing iron absorption. 84 Direct measures of stored iron were similar in 2 groups of persons with hemochromatosis: those who consumed more than 100 g of alcohol daily and nondrinkers or moderate drinkers who consumed less than 100 g of alcohol daily; complications of alcoholism were common in the first group.…”

Section: Noniron Diet Itemsmentioning

confidence: 73%

How I treat hemochromatosis

Adams

Barton

2010

Blood

160

167

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Hemochromatosis is a common genetic disorder in which iron may progressively accumulate in the liver, heart, and other organs. The primary goal of therapy is iron depletion to normalize body iron stores and to prevent or decrease organ dysfunction. The primary therapy to normalize iron stores is phlebotomy. In this opinion article, we discuss the indications for and monitoring of phlebotomy therapy to achieve iron depletion, maintenance therapy, dietary and pharmacologic maneuvers that could reduce iron absorption, and the role of voluntary blood donation. (Blood. 2010;116(3):317-325)

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Section: Noniron Diet Itemsmentioning

confidence: 73%

How I treat hemochromatosis

Adams

Barton

2010

Blood

160

167

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“…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. …”

mentioning

confidence: 97%

“…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.…”

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confidence: 99%

Iron storage disease: Facts, fiction and progress

Beutler

2007

Blood Cells, Molecules, and Diseases

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There are many forms of iron storage disease, some hereditary and some acquired. The most common of the hereditary forms is HFE-associated hemochromatosis, and it is this disorder that is the main focus of this presentation. The body iron content is regulated by controlling absorption, and studies in the past decade have clarified, in part, how this regulation functions. A 25 amino acid peptide hepcidin is upregulated by iron and by inflammation, and it inhibits iron absorption and traps iron in macrophages by binding to and causing degradation of the iron transport protein ferroportin. Most forms of hemochromatosis results from dysregulation of hepcidin or defects of hepcidin or ferroportin themselves.Hereditary hemochromatosis was once considered to be very rare, but in the 1970s and 1980s, with the introduction of better diagnostic tests, it became to be considered the most common disease of Europeans. Controlled epidemiologic studies carried out in the last decade have shown, however, the disease itself actually is rare, and it is only the genotype and associated biochemical changes that are common. We do not understand why only a few homozygotes develop severe disease. It now seems unlikely that there are important modifying genes, and although alcohol is known to have some effect, excess drinking probably plays only a modest role in determining the hemochromatosis phenotype.Hereditary hemochromatosis is readily treated by phlebotomy. Secondary forms of the disease require chelation therapy, and the recent introduction of effective oral chelating agents is an important step forward in treating patients with disorders in which iron overload often proves to be fatal, such as thalassemia, myelodysplastic anemias, and dyserythropoietic anemias.While much has been learned about the regulation of iron homeostasis in the past decade, many mysteries remain and represent challenges that will keep us occupied for years to come.It is a great honor for me to present this lecture in memory of my good friend Bracha Ramot. It is because this lecture is in honor of Bracha that I do not feel the least bit uncomfortable speaking about iron storage diseases in a symposium entitled "Genomics and Molecular Biology of Hematopoietic Malignancies". I know that had it been possible to ask her whether this might be appropriate Bracha would have said: "Of course, Ernie. Talk about whatever you want to". That was her way. And, of course, Bracha was no stranger to iron metabolism. She was scientifically broad, a Renaissance hematologist. A MEDLINE search reveals 261 publications by Bracha and eight of those deal with iron --iron in thalassemia, iron in sideroblastic anemia, and iron in iron deficiency anemia.Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable...

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“…710027, 710260, respectively), as described previously (8). The ethanol content of the diet was gradually increased over an 8-day period (no ethanol for days 1-2, 1/4 the amount for days 3-4, and 1/2 the amount for days [5][6][7] to the full amount (36% of total calories as ethanol). Rats were exposed to the full amount of ethanol for 6 wk.…”

Section: Animal Experimentsmentioning

confidence: 99%

“…alcoholic liver disease; iron; liver injury; oxidative stress HEPCIDIN, A CIRCULATORY PEPTIDE synthesized by the liver, plays a central role in the regulation of iron metabolism by controlling the iron uptake from the intestine and iron release from macrophages (16,18,20). Both acute and chronic alcohol exposure downregulate hepcidin expression in the liver (3,5,(7)(8)(9)21). This results in an increase in the expression of iron transporters in the duodenum and the iron storage protein ferritin in the liver (8, 9).…”

mentioning

confidence: 99%

Regulation of liver hepcidin expression by alcohol in vivo does not involve Kupffer cell activation or TNF-α signaling

Harrison-Findik¹,

Klein²,

Evans³

et al. 2009

American Journal of Physiology-Gastrointestinal and Liver Physi

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Alcohol downregulates hepcidin expression in the liver leading to an increase in intestinal iron transport and liver iron storage. We have previously demonstrated that alcoholmediated oxidative stress is involved in the inhibition of hepcidin transcription by alcohol in vivo. Kupffer cells and TNF-␣ play a key role in alcohol-induced liver injury. The aim of this study was to define their involvement in the regulation of hepcidin expression by alcohol. Kupffer cells were inactivated or depleted by employing gadolinium chloride and liposomes containing clodronate, respectively. Rats pair fed with the alcohol-Lieber-DeCarli diet for 6 wk and mice fed with 20% ethanol in the drinking water for 1 wk were used as experimental models. Interestingly, alcohol downregulated hepcidin expression in the livers of rats and mice independent of gadolinium chloride or clodronate treatment. One week of alcohol treatment was sufficient to induce a significant increase in TNF-␣ levels and phosphorylation of NF-B subunit p65. The neutralization of TNF-␣ by specific antibodies inhibited p65 phosphorylation. However, neither the neutralization of TNF-␣ nor the lack of TNF-␣ receptor expression reversed alcohol-induced suppression of liver hepcidin expression. The level of alcohol-induced ROS in the liver was also undiminished following Kupffer cell inactivation or depletion. Our results demonstrate that alcohol-induced Kupffer cell activation and TNF-␣ signaling are not involved in the suppression of liver hepcidin expression by alcohol-mediated oxidative stress in vivo. Therefore, these findings suggest that alcohol acts within hepatocytes to suppress hepcidin expression and thereby influences iron homeostasis. alcoholic liver disease; iron; liver injury; oxidative stress HEPCIDIN, A CIRCULATORY PEPTIDE synthesized by the liver, plays a central role in the regulation of iron metabolism by controlling the iron uptake from the intestine and iron release from macrophages (16,18,20). Both acute and chronic alcohol exposure downregulate hepcidin expression in the liver (3,5,(7)(8)(9)21). This results in an increase in the expression of iron transporters in the duodenum and the iron storage protein ferritin in the liver (8, 9).The activation of Kupffer cells and inflammatory responses prime the liver for alcoholic liver disease (ALD) (1,23,25). The proinflammatory cytokine TNF-␣, mainly synthesized by Kupffer cells, plays a critical role in ethanol-induced liver injury (10,14,30). TNF-␣ has been reported to downregulate hepcidin expression in human hepatoma cells (17). However, LPS and the cytokines IL-1 and IL-6 induce liver hepcidin expression (11,17). Lou et al. (13) Besides cytokines, Kupffer cells activated following alcohol exposure also release reactive oxygen species (2,23,28). We have demonstrated that alcohol-mediated oxidative stress suppresses liver hepcidin expression and promoter activity by inhibiting the DNA-binding activity of the transcription factor, CCAAT/enhancer-binding protein ␣ (C/EBP ␣) in vivo (9). We investigat...

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Effects of Alcohol Consumption on Iron Metabolism in Mice with Hemochromatosis Mutations

Cited by 32 publications

References 24 publications

How I treat hemochromatosis

How I treat hemochromatosis

Iron storage disease: Facts, fiction and progress

Regulation of liver hepcidin expression by alcohol in vivo does not involve Kupffer cell activation or TNF-α signaling

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