Dysregulated expression of fatty acid oxidation enzymes and iron-regulatory genes in livers of Nrf2-null mice
Dysregulated expression of fatty acid oxidation enzymes and iron-regulatory genes in livers of Nrf2-null mice
复制标题
DOI：
10.1111/j.1440-1746.2012.07180.x
复制
发表时间：
2012-11-01
影响因子：
4.1
通讯作者：
Kamisako, Toshinori
中科院分区：
文献类型：
--
作者：
Tanaka, Yuji;Ikeda, Takanori;Kamisako, Toshinori
背景和目的：肝脏铁过量可能在非酒精性脂肪性肝炎(NASH)的发病机制中起一定作用。NRF2是抗氧化反应的主要调节因子。然而，Nrf2在脂质和铁稳态中的作用仍不清楚。方法：给野生型和Nrf2基因缺失的小鼠饲喂高脂饲料(4%大豆油)12周，(Ii)对照饲料(4%大豆油)8周，(Ii)对照饲料(0.5%羰基铁4周)，(Iii)高脂饲料(4%大豆油和16%猪油)12周，(Iv)高脂饲料8周，高脂饲料加0.5%酮基铁4周。12周后取出血液和肝脏。结果：与野生型对照小鼠相比，Nrf2基因缺失的对照组小鼠有升高肝脏甘油三酯的趋势。在HFD期间，Nrf2基因缺失小鼠的肝脏丙二醛水平和肝脏铁水平往往高于野生型小鼠。HFD与铁协同诱导野生型小鼠Ppara靶基因的表达，其中Acox和Cpt1在Nrf2缺失小鼠中的诱导作用减弱。野生型小鼠喂饲高铁饲料后，肝脏组织中的海普西丁和铁门蛋白1mRNA表达增加，而Nrf2基因缺失组小鼠肝脏中的表达无明显变化。结论：Nrf2基因缺失导致肝脏β-氧化酶和铁相关基因的mRNA表达异常，可能导致肝脏甘油三酯和铁浓度升高。NRF2可能在NASH的进展中起作用。
Background and Aim: Hepatic excessive iron may play a role in the pathogenesis of non-alcoholic steatohepatitis (NASH). Nrf2 is a master regulator of antioxidative responses. However, the role of Nrf2 in lipid and iron homeostasis remains unclear. Accordingly, it was examined how Nrf2 regulates lipid-related and iron-regulatory genes after feeding a high-fat diet (HFD) with iron.Methods: Wild-type and Nrf2-null mice were fed the following diets: (i) control diet (4% soybean oil) for 12 weeks, (ii) control diet for 8 weeks followed by control diet containing 0.5% carbonyl iron for 4 weeks, (iii) HFD (4% soybean oil and 16% lard) for 12 weeks, (iv) HFD for 8 weeks followed by HFD containing 0.5% carbonyl iron for 4 weeks. Blood and livers were removed after 12 weeks.Results: Nrf2-null control mice exhibited a tendency towards higher hepatic triglycerides compared to wild-type control mice. Hepatic malondialdehyde was higher and hepatic iron levels tended to be higher in Nrf2-null mice than wild-type counterparts while on a HFD. The HFD with iron synergistically induced mRNA expression of Ppara targets, including Acox and Cpt1 in wild-type mice, yet the induction was diminished in Nrf2-null mice. Hepatic hepcidin and ferroportin 1 mRNA expression were increased in wild-type mice after feeding a HFD with iron, but were unchanged in any group of Nrf2-null mice.Conclusions: Nrf2 deletion dysregulates hepatic mRNA expression of beta-oxidation enzymes and iron-related genes, possibly causing a trend for increased hepatic triglyceride and iron concentrations. Nrf2 may have roles in the progression of NASH.