School of Medicine, University of Queensland, Brisbane, Queensland, Australia; Gallipoli Medical Research Centre, Greenslopes Hospital, Brisbane, Queensland, Australia; Department of Gastroenterology and Hepatology, Princess Alexandra Hospital, Brisbane, Queensland, Australia.
Alcohol Clin Exp Res. 2013 Oct;37(10):1619-31. doi: 10.1111/acer.12155. Epub 2013 Jun 6.
Combined iron overload and alcohol may promote synergistic chronic liver injury and toxicity. The role of specific dietary fats in influencing the development of co-toxic alcoholic liver disease needs further evaluation and is investigated in this study.
Wild-type (WT) and the iron-loaded Hfe-null (Hfe(-/-) ) mice were fed chow (CC), a AIN-93G standard control (SC), or a corn oil-modified, AIN-93G-based (CO) diet with or without the addition of 20% ethanol (EtOH) in the drinking water for 8 weeks and assessed for liver injury.
WT mice on CC, SC, and CO diets had no liver injury, although mild steatosis developed in the SC and CO groups. The addition of EtOH resulted in mild steatohepatitis in WT mice fed SC but not those on a CO diet. EtOH administration in Hfe(-/-) animals on the CC and SC diets caused marked oxidative stress, inflammatory activity, and subsinusoidal and portal-portal tract linkage fibrosis with significant up-regulation of genes involved in cellular stress signaling and fibrogenic pathways. These effects were abrogated in the CO-fed mice, despite elevated serum EtOH levels and hepatic iron concentrations, reduced hepatic glutathione and mitochondrial superoxide dismutase activities. Feeding with the CO diet led to increased hepatic glutathione peroxidase and catalase activities and attenuated alcohol-induced hepatic steatosis in the Hfe(-/-) animals. Iron and EtOH feeding markedly reduced p-STAT3 and p-AMPK protein levels, but this effect was significantly attenuated when a CO diet was consumed.
A CO-based diet is protective against combined EtOH- and iron-induced liver toxicity, likely via attenuation of hepatic steatosis and oxidative stress and may have a role in the prevention of fibrosis development in chronic liver disease.
铁过载与酒精联合可能会促进协同性慢性肝损伤和毒性。特定膳食脂肪在影响协同性酒精性肝病发展中的作用需要进一步评估，本研究对此进行了探讨。
野生型（WT）和铁负荷 Hfe 基因敲除（Hfe(-/-)）小鼠分别喂食标准对照饲料（CC）、AIN-93G 标准对照饲料（SC）或玉米油改良的 AIN-93G 基础饲料（CO），并在饮用水中添加或不添加 20%乙醇（EtOH），喂养 8 周后评估肝脏损伤情况。
WT 小鼠在 CC、SC 和 CO 饮食下没有发生肝损伤，尽管 SC 和 CO 组出现轻度脂肪变性。在 SC 饮食喂养的 WT 小鼠中，EtOH 的添加导致轻度脂肪性肝炎，但 CO 饮食喂养的 WT 小鼠没有出现这种情况。在 CC 和 SC 饮食喂养的 Hfe(-/-) 动物中，EtOH 给药导致明显的氧化应激、炎症活性、窦周隙和门管区纤维连接，细胞应激信号和纤维发生途径相关基因显著上调。这些影响在 CO 饮食喂养的小鼠中被消除，尽管血清 EtOH 水平和肝铁浓度升高，肝谷胱甘肽和线粒体超氧化物歧化酶活性降低。CO 饮食喂养导致 Hfe(-/-) 动物的肝谷胱甘肽过氧化物酶和过氧化氢酶活性增加，并减轻酒精引起的肝脂肪变性。铁和 EtOH 喂养显著降低了 p-STAT3 和 p-AMPK 蛋白水平，但当摄入 CO 饮食时，这种作用显著减弱。
CO 饮食可预防 EtOH 和铁引起的肝毒性，可能通过减轻肝脂肪变性和氧化应激发挥作用，并可能在慢性肝病纤维化发展的预防中发挥作用。
