Department of Internal Medicine I, University Hospital Ulm, Germany.
J Pathol. 2013 Dec;231(4):532-42. doi: 10.1002/path.4221. Epub 2013 Oct 15.
The liver is the central regulator of iron metabolism and accordingly, chronic liver diseases often lead to systemic iron overload due to diminished expression of the iron-regulatory hormone hepcidin. To study the largely unknown regulation of iron metabolism in the context of hepatic disease, we used two established models of chronic liver injury, ie repeated carbon tetrachloride (CCl(4)) or thioacetamide (TAA) injections. To determine the impact of CCAAT/enhancer-binding protein (C/EBP)-homologous protein (CHOP) on hepcidin production, the effect of a single TAA injection was determined in wild-type and CHOP knockout mice. Furthermore, CHOP and hepcidin expression was assessed in control subjects and patients with alcoholic liver disease. Both chronic injury models developed a distinct iron overload in macrophages. TAA-, but not CCl(4) - injected mice displayed additional iron accumulation in hepatocytes, resulting in a significant hepatic and systemic iron overload which was due to suppressed hepcidin levels. C/EBPα signalling, a known hepcidin inducer, was markedly inhibited in TAA mice, due to lower C/EBPα levels and overexpression of CHOP, a C/EBPα inhibitor. A single TAA injection resulted in a long-lasting (> 6 days) suppression of hepcidin levels and CHOP knockouts (compared to wild-types) displayed significantly attenuated hepcidin down-regulation in response to acute TAA administration. CHOP mRNA levels increased 5-fold in alcoholic liver disease patients versus controls (p < 0.005) and negatively correlated with hepcidin expression. Our results establish CHOP as an important regulator of hepatic hepcidin expression in chronic liver disease. The differences in iron metabolism between the two widely used fibrosis models likely reflect the differential regulation of hepcidin expression in human liver disease.
肝脏是铁代谢的中央调节器官，因此，慢性肝脏疾病常由于铁调节激素铁调素表达减少而导致全身铁过载。为了研究肝脏疾病背景下铁代谢的大部分未知调节，我们使用了两种已建立的慢性肝损伤模型，即反复四氯化碳（CCl 4 ）或硫代乙酰胺（TAA）注射。为了确定CCAAT/增强子结合蛋白（C/EBP）-同源蛋白（CHOP）对铁调素产生的影响，在野生型和 CHOP 敲除小鼠中确定了单次 TAA 注射的影响。此外，还评估了 CHOP 和铁调素在对照受试者和酒精性肝病患者中的表达。两种慢性损伤模型均在巨噬细胞中引起明显的铁过载。TAA-，但不是 CCl 4 -注射小鼠在肝细胞中显示出额外的铁积累，导致显著的肝和全身铁过载，这是由于铁调素水平降低所致。C/EBPα信号转导，已知的铁调素诱导剂，在 TAA 小鼠中明显受到抑制，这是由于 C/EBPα水平降低和 C/EBPα抑制剂 CHOP 的过表达所致。单次 TAA 注射导致铁调素水平的长时间（> 6 天）抑制，并且 CHOP 敲除（与野生型相比）在急性 TAA 给药时显示出铁调素下调的显著减弱。与对照组相比，酒精性肝病患者的 CHOP mRNA 水平增加了 5 倍（p < 0.005），并且与铁调素表达呈负相关。我们的结果确立了 CHOP 作为慢性肝脏疾病中铁调素表达的重要调节剂。两种广泛使用的纤维化模型之间的铁代谢差异可能反映了人类肝脏疾病中铁调素表达的差异调节。
