Chronic liver diseases, including cancer, are characterized by inflammation and elevated serum ferritin (SF). However, the causal-relationship remains unclear. This study used primary rat hepatic stellate cells (HSC) as a model to investigate effects of physiological SF concentrations (10, 100 and 1000 pM) because HSCs play a central role in the development and progression of liver fibrosis. Physiological concentrations of SF, either horse SF or human serum, induced pro-inflammatory cytokine IL1β, IL6 and TNFα secretion in rat activated HSCs (all p<0.05). By contrast, treatment did not alter activation marker αSMA expression. The presence of SF markedly enhanced expression of Grp78 mRNA (p<0.01). Furthermore, transient knock down of Grp78 by endotoxin EGFSubA abolished SF-induced IL1β and TNFα secretion in activated HSCs (all p<0.05). In conclusion, our results showed that at physiological concentrations SF functions as a pro-inflammatory mediator in primary rat HSCs. We also provide a molecular basis for the action of SF and identified Grp78-associated ER stress pathways as a novel potential therapeutic target for resolution of fibrosis and possible prevention of liver cancer.
Diabetic patients are at high risk of developing anemia; however, pharmacological doses of iron supplementation may vary greatly depending on diabetes-related complications. The aim of this study was to investigate the dose-dependent effect of iron on glucose disposal with a special focus on endoplasmic reticular (ER) stress, iron metabolism, and insulin signalling pathways. Diabetes was induced in overnight fasted rats by intraperitoneal (i.p.) injections of 40 mg kg(-1) streptozotocin (STZ) and 100 mg kg(-1) nicotinamide. Diabetic rats were fed a standard diet (36.7 mg ferric iron per kg diet) or pharmacological doses of ferric citrate (0.5, 1, 2, and 3 g ferric iron per kg diet). Ferric citrate supplementation showed a dose-related effect on hepatic ER stress responses and total iron levels, which were associated with increased hepcidin and decreased ferroportin expressions. Iron-fed rats had increased sizes of their pancreatic islets and hyperinsulinemia compared to rats fed a standard diet. A western blot analysis revealed that iron feeding decreased total insulin receptor substrate 1 (IRS1), phosphorylated IRS1ser307, and AS160 but increased phosphorylated GSK-3β. Iron supplementation inhibited the nuclear translocation of AKT but promoted FOXO1 translocation to nuclei. Ferric citrate supplementation showed a dose-related effect on ER stress responses, hepatic iron, and the insulin signaling pathway. Adverse effects were more evident at high iron doses (>1 g ferric iron per kg diet), which is equivalent to a 60 kg human male consuming >500 mg elemental iron per day.
Objectives: Asians and Pacific Islanders have higher circulating serum ferritin (SF) compared with Caucasians but the clinical significance of this is unclear. There is a higher prevalence of metabolic syndrome (MetS) in Taiwanese Indigenous than Han Chinese. Genetically, Indigenous are related to Austronesians and account for 2 % of Taiwan's population. We tested the hypothesis that accumulation of Fe in the body contributes to the ethnic/racial disparities in MetS in Taiwan. Design: A population-based, cross-sectional study. Setting: National Nutrition and Health Survey in Taiwan and Penghu Island. Subjects: A total of 2638 healthy adults aged $19 years. Three ethnic groups were included. Results: Han Chinese and Indigenous people had comparable levels of SF. Austronesia origin was independently associated with MetS (OR 5 2?61, 95 % CI 2?02, 3?36). After multiple adjustments, the odds for MetS (OR 5 2?49, 95 % CI 1?15, 5?28) was significantly higher among Indigenous people in the highest SF tertile compared with those in the lowest tertile. Hakka and Penghu Islanders yielded the lowest risks (OR 5 1?08, 95 % CI 0?44, 2?65 and OR 5 1?21, 95 % CI 0?52, 2?78, respectively). Indigenous people in the highest SF tertile had increased risk for abnormal levels of fasting glucose (OR 5 2?34, 95 % CI 1?27, 4?29), TAG (OR 5 1?94, 95 % CI 1?11, 3?39) and HDL-cholesterol (OR 5 2?10, 95 % CI 1?18, 3?73) than those in the lowest SF tertile. Conclusions: Our results raise the possibility that ethnic/racial differences in body Fe store susceptibility may contribute to racial and geographic disparities in MetS.
Overall, the present results suggest a dose-related effect of ferric citrate supplementation on AGE metabolism, and this effect was more evident at high iron doses (>1 g of ferric iron/kg diet).
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