Pathways underlying iron accumulation in human nonalcoholic fatty liver disease
Pathways underlying iron accumulation in human nonalcoholic fatty liver disease
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DOI：
10.1093/ajcn/87.5.1374
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发表时间：
2008-05-01
影响因子：
7.1
通讯作者：
Weiss, Guenter
中科院分区：
文献类型：
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作者：
Aigner, Elmar;Theurl, Igor;Weiss, Guenter
背景：轻度铁超载常见于非酒精性脂肪性肝病(NAFLD)。目的：研究非酒精性脂肪性肝病(NAFLD)中铁蓄积的可能途径。设计：研究有(n=32)和无(n=29)铁超载、遗传性血色素沉着症(n=10)和对照组(n=20)的NAFLD患者肝脏和十二指肠关键铁分子的表达。结果：NAFLD患者肝组织铁输出蛋白铁蛋白-1(FP-1)和铁敏感分子血凝素(HJV)的表达明显降低。铁负荷过高的NAFLD患者体内铁调节多肽海普西丁的mRNA表达增加，与十二指肠FP-1的低表达相平行。NAFLD患者肝组织中肿瘤坏死因子-α(TNF-α)的mRNA和蛋白浓度明显升高，且与肝脏FP-1和HJV的mRNA呈负相关，与体重指数和肝组织海普西丁的mRNA呈正相关。相应地，肿瘤坏死因子-α可抑制HepG2细胞中FP-1和HJV基因的表达。结论：非酒精性脂肪性肝病患者血清铁蛋白、转铁蛋白饱和度和肿瘤坏死因子-α浓度降低，肝功能检查得到改善。结论：非酒精性脂肪性肝病患者体内铁蓄积可能是由于FP1表达下调和肝脏铁感应失效所致，表现为HJV表达降低。肿瘤坏死因子-α似乎在这些调节变化中发挥了作用。然而，铁负荷过高的NAFLD患者中海普西丁的形成增加会导致十二指肠FP-1表达减少，而肝脏FP-1的减少可能会使肝脏铁滞留永久化。静脉切开术为这些代谢紊乱提供了一种安全有效的治疗方法。
Background: Mild iron overload is frequently observed in nonalcoholic fatty liver disease (NAFLD).Objective: We aimed to study putative pathways underlying iron accumulation in NAFLD.Design: Hepatic and duodenal expression of critical iron molecules in NAFLD patients with (n = 32) and without (n = 29) iron overload, hereditary hemochromatosis (n = 10), and controls (n = 20) were investigated. Phlebotomy treatment was performed in 14 NAFLD patients.Results: The hepatic expressions of the iron-export protein ferroportin-1 (FP-1) and of the iron-sensing molecule hemojuvelin (HJV) were significantly lower in NAFLD patients. The mRNA expression of the iron-regulatory peptide hepcidin was increased in NAFLD patients with iron overload, which was paralleled by low duodenal FP-1 expression. Hepatic mRNA and serum protein concentrations of tumor necrosis factor-alpha (TNF-alpha) were increased in NAFLD patients and were inversely correlated with both liver FP-1 and HJV mRNA and positively associated with body mass index and hepatic hepcidin mRNA. Accordingly, TNF-alpha inhibited the FP-1 and HJV mRNA formation in HepG2 cells. Phlebotomy treatment of NALFD patients reduced serum ferritin, transferrin saturation, and TNF-alpha concentrations and improved liver function tests.Conclusions: Iron accumulation in NAFLD may result from an impaired iron export due to down-regulation of FP1 and ineffective hepatic iron sensing, as indicated by low HJV expression. TNF-alpha appears to play a role in exerting these regulatory changes. Increased hepcidin formation in iron-overloaded NAFLD patients, however, results in decreased duodenal FP-1 expression, whereas a reduction in liver FP-1 may perpetuate hepatic iron retention. Phlebotomy offers a safe and efficient therapy for these metabolic disturbances.