Transcription factor Nrf2 regulates SHP and lipogenic gene expression in hepatic lipid metabolism
Transcription factor Nrf2 regulates SHP and lipogenic gene expression in hepatic lipid metabolism
复制标题
DOI：
10.1152/ajpgi.00322.2010
复制
发表时间：
2010-12-01
影响因子：
4.5
通讯作者：
Wang, Li
中科院分区：
文献类型：
--
作者：
Huang, Jiansheng;Tabbi-Anneni, Imene;Wang, Li
核因子红细胞2相关因子2（Nrf 2）在细胞抗内源性和外源性应激中起着关键作用。在这里，我们建立了一个新的Nrf 2，核受体小异源二聚体伴侣（SHP; NROB 2），脂肪生成基因和肝脏脂质稳态之间的分子联系。在小鼠中缺失Nrf 2（Nrf 2（-/-））导致肝脏重量减轻，肝脏三酰甘油脂肪酸含量降低，以及伴随的6月龄时血清VLDL-甘油三酯（TG）、HDL胆固醇和酮体水平升高。在高脂激发后，Nrf 2（-/-）小鼠的肝脏重量和肝脏TG含量始终较低。这种表型伴随着较老的Nrf 2（-/-）小鼠中脂质合成和摄取基因的下调以及脂质氧化基因的上调。有趣的是，SHP表达在Nrf 2（+/+）小鼠中随着年龄的增长而诱导，但在Nrf 2缺乏时降低。Nrf 2激活剂对Nrf 2的强制表达和激活一致地诱导SHP表达，并且Nrf 2被鉴定为SHP基因转录的新激活剂。我们还确定了PPAR-gamma、Fas、Scd 1和Srebp-1作为Nrf 2激活的直接靶点。这些发现提供了证据Nrf 2的作用，通过转录激活SHP和脂肪生成基因表达的调节肝脏脂质稳态。
Nuclear factor erythroid-2 related factor 2 (Nrf2) plays a pivotal role in cytoprotection against both endogenous and exogenous stresses. Here, we establish a novel molecular link between Nrf2, nuclear receptor small heterodimer partner (SHP; NROB2), lipogenic genes, and hepatic lipid homeostasis. Deletion of Nrf2 (Nrf2(-/-)) in mice resulted in a reduced liver weight, a decrease in fatty acid content of hepatic triacylglycerol, as well as concomitant increases in the levels of serum VLDL-triglyceride (TG), HDL cholesterol, and ketone bodies at 6 mo of age. Liver weight and hepatic TG content were consistently lower in Nrf2(-/-) mice upon a high-fat challenge. This phenotype was accompanied by downregulation of genes in lipid synthesis and uptake and upregulation of genes in lipid oxidation in older Nrf2(-/-) mice. Interestingly, SHP expression was induced with age in Nrf2(+/+) mice but decreased by Nrf2 deficiency. Forced expression and activation of Nrf2 by Nrf2 activators consistently induced SHP expression, and Nrf2 was identified as a novel activator of the SHP gene transcription. We also identified PPAR-gamma, Fas, Scd1, and Srebp-1 as direct targets of Nrf2 activation. These findings provide evidence for a role of Nrf2 in the modulation of hepatic lipid homeostasis through transcriptional activation of SHP and lipogenic gene expression.