生命金属元素鉄の新たな役割と治療応用

Iron is the most abundant trace metal and indispensable for the biogenicity of living organisms. Iron deficiency anemia is often observed in iron-related disorders, and therefore, proactive iron intake is recommended. In contrast, iron causes oxidative stress by catalyzing the Fenton reaction. Recent evidence suggests that iron is involved in the pathophysiology of non-iron-accumulating diseases, and the role of iron has been revisited. In the last three decades, many studies have shown that iron content is associated with diabetes and that high iron intake increases the risk of diabetes onset. Iron reduction by phlebotomy or iron chelators ameliorates insulin sensitivity and secretion. Several studies have shown that high iron levels are also associated with obesity. Therefore, we speculate that iron reduction could exert a favorable effect on obesity. As expected, iron chelators mitigated obesity by inhibiting inflammatory cytokines and oxidative stress in KKAy mice. We advocate that “iron stress” is related to iron-dependent inflammation and oxidative stress, and have reported that iron stress is involved in kidney disease, sarcopenia, vascular dysfunction, and so on. However, non-specific iron reduction always causes iron-deficient adverse effects, such as anemia, and it is difficult to adopt a clinical application. Macrophage plays a critical role in chronic inflammation including obesity and diabetes. M1 inflammatory macrophages exhibit an iron-retention phenotype with elevated H-ferritin（ FTH） expression. Mice with macrophage-specific FTH deletion（FTHKO） showed reduced iron concentrations in macrophages, without anemia. HFD- induced obesity and diabetes were alleviated in FTHKO mice by inhibiting inflammation and oxidative stress in adipose tissue, similar to the effect of systemic iron reduction. Therefore, macrophages are the main source of iron stress, leading to new therapeutic strategies for controlling the iron levels in macrophages.