Influence of short-time feeding of rats with an iron-deficient diet on their hepatic gene expression profiles

Iron deficiency-induced anemia is generally a representative nutritional problem in most populations. We reported that the anemia due to dietary iron deficiency causes a variety of changes in nutrient metabolism, even leading to apoptosis as a result of associated endoplasmic reticulum (ER) stress in the rat liver. On the other hand, it appears that non-anemic iron-deficiency causes no serious problem because no appreciable down-regulation of hemoglobin synthesis occurs. Biochemically, iron is essential for activation of cytochrome-related enzymes and its deficiency should yield some physiological problems. We performed a comprehensive transcriptome analysis to define the effects of non-anemic iron deficiency on hepatic gene expression. Four-week-old rats were fed a low-iron diet (ca. 3 ppm iron) for 2 days. These rats were compared with those fed a control diet (48 ppm iron) by pair feeding. On day 3, the rats were sacrificed under anesthesia, and their livers were dissected for DNA microarray analysis. Rats in the iron-deficient diet group, showed that their serum ferritin and iron levels decreased with an increase in the serum total iron binding capacity (TIBC) level, while the hemoglobin level was not changed. In the DNA microarray study, we identified 91 up-regulated and 186 down-regulated probe sets that characterized the iron-deficient diet group. In the up-regulated probe sets, genes involved in glucose and lipid metabolic processes were significantly enriched, whereas genes related to organic acid metabolic process, cellular ketone metabolic process, lipid metabolic process, oxidation reduction, response to drug, response to extracellular stimulus and gas transport were significantly enriched in the down-regulated probe sets. These results suggest that even the non-anemic iron-deficiency exerts various influences on nutrient metabolisms in the liver.缺铁性贫血是多数人群中典型的营养性问题。我们此前的研究显示，膳食性缺铁引发的贫血会导致营养代谢发生多种改变，甚至会因大鼠肝脏伴随的内质网（endoplasmic reticulum, ER）应激而诱发细胞凋亡。另一方面，非贫血性缺铁似乎不会引发严重问题，因为其不会导致血红蛋白合成出现显著下调。从生物化学角度而言，铁是细胞色素相关酶激活所必需的物质，缺铁会引发一系列生理异常。本研究通过全面的转录组分析，旨在明确非贫血性缺铁对肝脏基因表达的影响。将4周龄大鼠饲喂低铁饲料（铁含量约3ppm），持续2天；通过配对饲喂方式，将该组大鼠与饲喂对照饲料（铁含量48ppm）的大鼠进行对照。于第3天对大鼠实施麻醉并处死，摘取肝脏用于DNA微阵列分析。缺铁饲料组大鼠的血清铁蛋白与血清铁水平均出现下降，且血清总铁结合力（total iron binding capacity, TIBC）水平升高，而血红蛋白水平未发生改变。在DNA微阵列分析中，本研究共鉴定出91个上调探针集与186个下调探针集，以此作为缺铁饲料组的特征基因集。上调探针集中，参与糖脂代谢过程的基因显著富集；而下调探针集中，则显著富集了与有机酸代谢、细胞酮体代谢、脂质代谢、氧化还原、药物应答、细胞外刺激应答以及气体运输相关的基因。上述结果表明，即便为非贫血性缺铁，也会对肝脏的营养代谢产生多方面影响。