Abstract
This paper is dedicated to the memory of our wonderful colleague Professor Alfredo Colonna, who passed away the same day of its acceptance. Fatty liver accumulation, inflammatory process and insulin resistance appear to be crucial in non-alcoholic fatty liver disease (NAFLD), nevertheless emerging findings pointed an important role also for iron overload. Here, we investigate the molecular mechanisms of hepatic iron metabolism in the onset of steatosis to understand whether its impairment could be an early event of liver inflammatory injury. Rats were fed with control diet or high fat diet (HFD) for 5 or 8 weeks, after which liver morphology, serum lipid profile, transaminases levels and hepatic iron content (HIC), were evaluated. In liver of HFD fed animals an increased time-dependent activity of iron regulatory protein 1 (IRP1) was evidenced, associated with the increase in transferrin receptor-1 (TfR1) expression and ferritin down-regulation. Moreover, ferroportin (FPN-1), the main protein involved in iron export, was down-regulated accordingly with hepcidin increase. These findings were indicative of an increased iron content into hepatocytes, which leads to an increase of harmful free-iron also related to the reduction of hepatic ferritin content. The progressive inflammatory damage was evidenced by the increase of hepatic TNF-α, IL-6 and leptin, in parallel to increased iron content and oxidative stress. The major finding that emerged of this study is the impairment of iron homeostasis in the ongoing and sustaining of liver steatosis, suggesting a strong link between iron metabolism unbalance, inflammatory damage and progression of disease.
Highlights
The progression of non-alcoholic fatty liver disease (NAFLD) from a benign pathology as steatosis to more severe forms of liver diseases is determined by many factors or ‘‘hits’’ which may act in sequence or parallel, as recently proposed [1]
Maintenance of iron homeostasis is largely accomplished by the transferrin receptor -1 (TfR-1), which allows iron uptake, and by ferritin, which is crucial to sequester this metal in a non-toxic form [7]
The levels of these and other proteins involved in iron metabolism are mainly regulated posttranscriptionally by interaction between the iron regulatory proteins (IRP1 and IRP2) and stem-loop structures, termed iron responsive elements (IREs), located in the 59-untranslated region (UTR) of ferritin mRNAs and in the 39-UTR of TfR mRNA [8,9]
Summary
The progression of non-alcoholic fatty liver disease (NAFLD) from a benign pathology as steatosis to more severe forms of liver diseases (i.e. hepatitis, fibrosis, cirrhosis, hepatocarcinoma) is determined by many factors or ‘‘hits’’ which may act in sequence or parallel, as recently proposed [1]. Maintenance of iron homeostasis is largely accomplished by the transferrin receptor -1 (TfR-1), which allows iron uptake, and by ferritin, which is crucial to sequester this metal in a non-toxic form [7]. The levels of these and other proteins involved in iron metabolism are mainly regulated posttranscriptionally by interaction between the iron regulatory proteins (IRP1 and IRP2) and stem-loop structures, termed iron responsive elements (IREs), located in the 59-untranslated region (UTR) of ferritin mRNAs and in the 39-UTR of TfR mRNA [8,9]. Besides the intracellular iron concentration, IRPs RNA binding activity is regulated by iron independent factors, such as oxidative stress [14], nitric oxide signalling [15], viral infection [16], hypoxia/reoxygenation [17,18] and estrogens [19]
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