NF-E2-Related Factor 1 (Nrf1) Serves as a Novel Regulator of Hepatic Lipid Metabolism through Regulation of the Lipin1 and PGC-1β Genes
NF-E2-Related Factor 1 (Nrf1) Serves as a Novel Regulator of Hepatic Lipid Metabolism through Regulation of the Lipin1 and PGC-1β Genes
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DOI：
10.1128/mcb.06706-11
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发表时间：
2012-07-01
影响因子：
5.3
通讯作者：
Yamamoto, Masayuki
中科院分区：
文献类型：
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作者：
Hirotsu, Yosuke;Hataya, Nami;Yamamoto, Masayuki
肝脏脂质代谢受到复杂的调控，在转录水平上这种调控过程的扰动会导致病理状况。nf - e2相关因子1 （Nrf1）是cap'n'collar （CNC）转录因子家族的一员。已知肝细胞特异性Nrf1基因条件敲除小鼠会发生肝脂肪变性，但Nrf1如何促进脂质稳态仍不清楚。因此，在本研究中，我们检测了nrf1缺陷小鼠肝脏的基因表达谱。基于分析结果的通路分析显示，Nrf1缺乏小鼠肝脏中脂质代谢、氨基酸代谢和线粒体呼吸功能相关基因的表达水平下降，表明Nrf1缺乏对各种代谢途径产生了深远的影响。我们发现Nrf1缺乏导致转录辅助激活因子基因Lipin1和PGC-1 β（过氧化物酶体增殖物激活受体γ辅助激活因子1 β）的表达减少。染色质免疫沉淀分析表明，Nrf1与脂质和PGC-1 β基因调控区域的抗氧化反应元件（AREs）结合，Nrf1与AREs结合激活报告基因转录。因此，这些结果确定Nrf1是Lipinl和PGC-1 β基因的新调节剂，为Nrf1在肝脏脂质代谢中的功能提供了新的见解。
Hepatic lipid metabolism is under elaborate regulation, and perturbations in this regulatory process at the transcriptional level lead to pathological conditions. NF-E2-related factor 1 (Nrf1) is a member of the cap'n'collar (CNC) transcription factor family. Hepatocyte-specific Nrf1 gene conditional-knockout mice are known to develop hepatic steatosis, but it remains unclear how Nrf1 contributes to the lipid homeostasis. Therefore, in this study we examined the gene expression profiles of Nrf1-deficient mouse livers. A pathway analysis based on the profiling results revealed that the levels of expression of the genes related to lipid metabolism, amino acid metabolism, and mitochondrial respiratory function were decreased in Nrf1-deficient mouse livers, indicating the profound effects that the Nrf1 deficiency conferred to various metabolic pathways. We discovered that the Nrf1 deficiency leads to the reduced expression of the transcriptional coactivator genes Lipin1 and PGC-1 beta (for peroxisome proliferator-activated receptor gamma coactivator 1 beta). Chromatin immunoprecipitation analyses showed that Nrf1 binds to the antioxidant response elements (AREs) in regulatory regions of the Lipinl and PGC-1 beta genes and the binding of Nrf1 to the AREs activates reporter gene transcription. These results thus identified Nrf1 to be a novel regulator of the Lipinl and PGC-1 beta genes, providing new insights into the Nrf1 function in hepatic lipid metabolism.