Abstract
Iron is an essential trace element whose absorption is usually tightly regulated in the duodenum. HFE-related hereditary hemochromatosis (HH) is characterized by abnormally low expression of the iron-regulatory hormone, hepcidin, which results in increased iron absorption. The liver is crucial for iron homeostasis as it is the main production site of hepcidin. The aim of this study was to explore and compare the genome-wide transcriptome response to Hfe deficiency and dietary iron overload in murine liver and duodenum. Illumina™ arrays containing over 47,000 probes were used to study global transcriptional changes. Quantitative RT-PCR (Q-RT-PCR) was used to validate the microarray results. In the liver, the expression of 151 genes was altered in Hfe−/− mice while dietary iron overload changed the expression of 218 genes. There were 173 and 108 differentially expressed genes in the duodenum of Hfe−/− mice and mice with dietary iron overload, respectively. There was 93.5% concordance between the results obtained by microarray analysis and Q-RT-PCR. Overexpression of genes for acute phase reactants in the liver and a strong induction of digestive enzyme genes in the duodenum were characteristic of the Hfe-deficient genotype. In contrast, dietary iron overload caused a more pronounced change of gene expression responsive to oxidative stress. In conclusion, Hfe deficiency caused a previously unrecognized increase in gene expression of hepatic acute phase proteins and duodenal digestive enzymes.
Highlights
Iron plays crucial roles in cellular metabolism but, in excess, it can catalyze the formation of free radicals leading to oxidative stress and cell damage [1]
We used global microarray analysis to study gene expression in the liver and duodenum of Hfe2/2 mice and carbonyl iron loaded mice, and comparing it with that of wild-type mice fed a standard diet. This approach allowed the identification of genes whose expression is changed during iron overload and those genes whose expression is differentially influenced by lack of Hfe protein
The results revealed 86 induced genes and 65 repressed genes, using a cutoff value of 61.4-fold (Table 1 and Dataset S1). This cutoff value has been proposed as an adequate compromise above which there is a high correlation between microarray and Q-RT-PCR data, regardless of other factors such as spot intensity and cycle threshold [18]
Summary
Iron plays crucial roles in cellular metabolism but, in excess, it can catalyze the formation of free radicals leading to oxidative stress and cell damage [1]. Iron is absorbed in the duodenum, where it crosses the apical and basolateral membranes of absorptive enterocytes to enter the blood stream [2]. There is no regulated mechanism of iron excretion, and the absorption of iron must be tightly regulated to maintain iron balance. HFErelated hereditary hemochromatosis (HH, OMIM-235200) is an autosomal recessive disorder in which absorption of iron is inappropriately high [3,4]. HH is characterized by high transferrin saturation and low iron content in macrophages. Iron is deposited primarily in the parenchymal cells of various organs, the liver, and the pancreas, heart, skin, and testes, resulting in tissue damage and organ failure. Clinical complications in untreated HH patients include hepatic fibrosis, cirrhosis, hepatocellular carcinoma, diabetes, cardiomyopathy, hypogonadism, and arthritis [4]
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