Chronic activation of hepatic Nrf2 has no major effect on fatty acid and glucose metabolism in adult mice. Mus musculus

The transcription factor NF-E2-related factor 2 (Nrf2) induces cytoprotective genes, but has also been linked to the regulation of hepatic energy metabolism. In order to assess the pharmacological potential of hepatic Nrf2 activation in metabolic disease, Nrf2 was activated over 8 weeks in mice on Western diet using two different siRNAs against kelch-like ECH-associated protein 1 (Keap1), the inhibitory protein of Nrf2. Whole genome expression analysis followed by pathway analysis demonstrated that the suppression of Keap1 expression induced genes that are involved in anti-oxidative stress defense and biotransformation, pathways proving the activation of Nrf2 by the siRNAs against Keap1. The expression of neither fatty acid- nor carbohydrate-handling proteins was regulated by the suppression of Keap1. Metabolic profiling of the animals did also not show effects on plasma and hepatic lipids, energy expenditure or glucose tolerance by the activation of Nrf2. The data indicate that hepatic Nrf2 is not a major regulator of intermediary metabolism in mice. Overall design: Gene expression profile of mouse liver samples from 8-week-old male C57BL6/J mice (N=24) treated with liver-selective Keap1-specific siRNA (group 1: siKeap1-1, N=8; group 2: siKeap1-2, N=8) or unspecific scrambled control siRNA (group 3: siControl, N=8)

转录因子NF-E2相关因子2（Nrf2）可诱导细胞保护性基因的表达，同时亦与肝脏能量代谢的调控存在关联。为评估肝脏Nrf2激活在代谢性疾病中的药理学潜力，研究人员采用两种靶向kelch样ECH相关蛋白1（Keap1，Nrf2的抑制性蛋白）的小干扰RNA（siRNA），在喂食西式饮食的小鼠中持续激活Nrf2长达8周。全基因组表达分析结合通路分析结果显示，抑制Keap1的表达可诱导参与抗氧化应激防御与生物转化过程的基因，上述通路充分验证了靶向Keap1的siRNA可有效激活Nrf2。
靶向脂肪酸与碳水化合物代谢的蛋白表达均未受Keap1沉默的调控。
对实验动物的代谢轮廓分析同样表明，Nrf2激活并未对血浆与肝脏脂质水平、能量消耗或葡萄糖耐量产生显著影响。
本研究数据表明，在小鼠体内，肝脏Nrf2并非中间代谢的主要调控因子。
总体实验设计：采集8周龄雄性C57BL6/J小鼠的肝脏样本进行基因表达谱分析，总样本量为24只。实验小鼠被分为三组：肝脏选择性Keap1特异性siRNA处理组1（siKeap1-1，N=8）、处理组2（siKeap1-2，N=8），以及非特异性乱序对照siRNA处理组（siControl，N=8）