High Fat Diet Induces Liver Steatosis and Early Dysregulation of Iron Metabolism in Rats

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.

Reactive Oxygen and Nitrogen Species in Steatotic Hepatocytes: A Molecular Perspective on the Pathophysiology of Ischemia-Reperfusion Injury in the Fatty Liver

“…These findings indicate that the inflammatory aspect of NALFD could contribute to hepatocellular iron accumulation as well as augmentation of the LIP and hence ONS. Accordingly, leukocyte influx as well as increased hepatic TNF-a mRNA, malondialdehyde (MDA, a lipid peroxidation end product), and 3-nitrotyrosine (a protein nitration marker) levels were also observed in these high-fat diet-fed rats (132).…”

“…More specifically, exposure of HepG2 cells to persistently low levels of extracellular H 2 O 2 (to mimic a state of chronic inflammation such as NAFLD) activated IRP1 and augmented the LIP (8). Moreover, rats that were fed a high-fat diet showed enhanced IRP1 activity, increased transferritin receptor 1 expression, decreased ferritin levels, and an increase in hepatic total iron content (132). These findings indicate that the inflammatory aspect of NALFD could contribute to hepatocellular iron accumulation as well as augmentation of the LIP and hence ONS.…”

The SRE Motif in the Human PNPLA3 Promoter (−97 to −88 bp) Mediates Transactivational Effects of SREBP‐1c

“…SD rats were fasted for 24 h and then refed for 48 h, n = 4). The other 10 rats were randomly assigned to feeding on a normal diet (ND) (n = 5, consisting of 10% fat) or a high‐fat diet (HFD) (n = 5, consisting of 60% fat) to develop NAFLD for5 weeks (Meli et al, ) after which steatosis was evaluated by oil red O staining. All procedures were performed in conformity with the Public Health Service (PHS) Policy, and the animal protocol was approved by the Sun Yat‐Sen University Institutional Animal Care and Use Committee.…”

Mechanisms Linking Glucose Homeostasis and Iron Metabolism Toward the Onset and Progression of Type 2 Diabetes

“…Animals fed a high-fat diet had increased activity of iron regulatory protein 1 in the liver and an increase in TfR1 expression (25). The high-fat diet also resulted in the increased secretion of hepcidin and the downregulation of FPN1, factors linked to increased intrahepatic deposition of iron (25).…”