PDF(Pubmed)
Abstract：
Understanding the role of iron in ethanol-derived hepatic stress could help elucidate the efficacy of dietary or clinical interventions designed to minimize liver damage from chronic alcohol consumption. We hypothesized that normal levels of iron are involved in ethanol-derived liver damage and reduced dietary iron intake would lower the damage caused by ethanol. We used a pair-fed mouse model utilizing basal Lieber-DeCarli liquid diets for 22 weeks to test this hypothesis. In our mouse model, chronic ethanol exposure led to mild hepatic stress possibly characteristic of early-stage alcoholic liver disease, seen as increases in liver-to-body weight ratios. Dietary iron restriction caused a slight decrease in non-heme iron and ferritin (FeRL) expression while it increased transferrin receptor 1 (TfR1) expression without changing ferroportin 1 (FPN1) expression. It also elevated protein lysine acetylation to a more significant level than in ethanol-fed mice under normal dietary iron conditions. Interestingly, iron restriction led to an additional reduction in nicotinamide adenine dinucleotide (NAD+) and NADH levels. Consistent with this observation, the major mitochondrial NAD+-dependent deacetylase, NAD-dependent deacetylase sirtuin-3 (SIRT3), expression was significantly reduced causing increased protein lysine acetylation in ethanol-fed mice at normal and low-iron conditions. In addition, the detection of superoxide dismutase 1 and 2 levels (SOD1 and SOD2) and oxidative phosphorylation (OXPHOS) complex activities allowed us to evaluate the changes in antioxidant and energy metabolism regulated by ethanol consumption at normal and low-iron conditions. We observed that the ethanol-fed mice had mild liver damage associated with reduced energy and antioxidant metabolism. On the other hand, iron restriction may exacerbate certain activities of ethanol further, such as increased protein lysine acetylation and reduced antioxidant metabolism. This metabolic change may prove a barrier to the effectiveness of dietary reduction of iron intake as a preventative measure in chronic alcohol consumption.
摘要：
了解铁在乙醇衍生的肝应激中的作用可能有助于阐明旨在减少慢性饮酒对肝损伤的饮食或临床干预措施的功效。我们假设正常水平的铁与乙醇引起的肝损伤有关，减少饮食中铁的摄入量会降低乙醇引起的损伤。我们使用双食小鼠模型，利用基础Lieber-DeCarli液体饮食22周来检验这一假设。在我们的老鼠模型中,慢性乙醇暴露导致轻度肝应激可能是早期酒精性肝病的特征，被视为肝脏与体重比的增加。饮食铁限制导致非血红素铁和铁蛋白（FeRL）表达略有下降，而增加了转铁蛋白受体1（TfR1）的表达，而不改变铁转运蛋白1（FPN1）的表达。在正常饮食铁条件下，与乙醇喂养的小鼠相比，它还将蛋白质赖氨酸乙酰化提高到了更高的水平。有趣的是,铁限制导致烟酰胺腺嘌呤二核苷酸（NAD）和NADH水平的额外降低。与这一观察一致，主要的线粒体NAD+依赖性脱乙酰酶，NAD依赖性去乙酰化酶sirtuin-3（SIRT3），在正常和低铁条件下，乙醇喂养小鼠的表达显着降低，导致蛋白质赖氨酸乙酰化增加。此外,超氧化物歧化酶1和2水平（SOD1和SOD2）和氧化磷酸化（OXPHOS）复合物活性的检测使我们能够评估正常和低铁条件下乙醇消耗调节的抗氧化剂和能量代谢的变化。我们观察到乙醇喂养的小鼠具有与能量和抗氧化剂代谢降低相关的轻度肝损伤。另一方面,铁限制可能会进一步加剧乙醇的某些活动，如增加蛋白质赖氨酸乙酰化和减少抗氧化剂代谢。这种代谢变化可能证明是饮食减少铁摄入量作为慢性饮酒预防措施的有效性的障碍。
