Department of Pathology (Division of Experimental Pathology), University of Pittsburgh, Pennsylvania, United States; Pittsburgh Liver Research Center, University of Pittsburgh, Pennsylvania, United States.
Department of Medicine University of California at Los Angeles, Los Angeles, CA, United States; Department of Pathology and Laboratory Medicine, University of California at Los Angeles, Los Angeles, CA, United States.
J Hepatol. 2017 Aug;67(2):360-369. doi: 10.1016/j.jhep.2017.03.012. Epub 2017 Mar 22.
BACKGROUND & AIMS: Iron overload disorders such as hereditary hemochromatosis and iron loading anemias are a common cause of morbidity from liver diseases and increase risk of hepatic fibrosis and hepatocellular carcinoma (HCC). Treatment options for iron-induced damage are limited, partly because there is lack of animal models of human disease. Therefore, we investigated the effect of iron overload in liver-specific β-catenin knockout mice (KO), which are susceptible to injury, fibrosis and tumorigenesis following chemical carcinogen exposure.
Iron overload diet was administered to KO and littermate control (CON) mice for various times. To ameliorate an oxidant-mediated component of tissue injury, N-Acetyl-L-(+)-cysteine (NAC) was added to drinking water of mice on iron overload diet.
KO on iron diet (KO +Fe) exhibited remarkable inflammation, followed by steatosis, oxidative stress, fibrosis, regenerating nodules and occurrence of occasional HCC. Increased injury in KO +Fe was associated with activated protein kinase B (AKT), ERK, and NF-κB, along with reappearance of β-catenin and target gene Cyp2e1, which promoted lipid peroxidation and hepatic damage. Addition of NAC to drinking water protected KO +Fe from hepatic steatosis, injury and fibrosis, and prevented activation of AKT, ERK, NF-κB and reappearance of β-catenin.
The absence of hepatic β-catenin predisposes mice to hepatic injury and fibrosis following iron overload, which was reminiscent of hemochromatosis and associated with enhanced steatohepatitis and fibrosis. Disease progression was notably alleviated by antioxidant therapy, which supports its chemopreventive role in the management of chronic iron overload disorders.
Lack of animal models for iron overload disorders makes it hard to study the disease process for improving therapies. Feeding high iron diet to mice that lack the β-catenin gene in liver cells led to increased inflammation followed by fat accumulation, cell death and wound healing that mimicked human disease. Administration of an antioxidant prevented hepatic injury in this model.
铁过载疾病，如遗传性血色素沉着症和铁过载性贫血，是导致肝脏疾病发病率增加并增加肝纤维化和肝细胞癌（HCC）风险的常见原因。铁诱导损伤的治疗选择有限，部分原因是缺乏人类疾病的动物模型。因此，我们研究了肝特异性β-连环蛋白敲除（KO）小鼠中铁过载的影响，这些小鼠在化学致癌物暴露后易受伤、纤维化和发生肿瘤。
用铁过载饮食喂养 KO 和同窝对照（CON）小鼠不同时间。为了改善组织损伤的氧化应激成分，将 N-乙酰-L-（+）-半胱氨酸（NAC）添加到铁过载饮食的小鼠饮用水中。
铁饮食的 KO（KO+Fe）表现出明显的炎症，随后是脂肪变性、氧化应激、纤维化、再生结节和偶尔发生 HCC。KO+Fe 中的损伤增加与蛋白激酶 B（AKT）、细胞外信号调节激酶（ERK）和核因子-κB（NF-κB）的激活有关，同时β-连环蛋白和靶基因 Cyp2e1 的重新出现促进了脂质过氧化和肝损伤。将 NAC 添加到饮用水中可防止 KO+Fe 发生肝脂肪变性、损伤和纤维化，并防止 AKT、ERK、NF-κB 和β-连环蛋白的重新出现。
肝内缺乏β-连环蛋白使铁过载后小鼠易发生肝损伤和纤维化，这与血色素沉着症相似，并伴有脂肪性肝炎和纤维化的加重。抗氧化治疗明显缓解了疾病的进展，支持其在慢性铁过载疾病管理中的化学预防作用。
缺乏铁过载疾病的动物模型使得研究改善治疗方法的疾病过程变得困难。用缺乏肝细胞中β-连环蛋白基因的小鼠喂养高铁饮食会导致炎症增加，随后是脂肪堆积、细胞死亡和伤口愈合，模拟人类疾病。该模型中抗氧化剂的给药可预防肝损伤。
