Identification of Nogo-B as a new molecular target of peroxisome proliferator-activated receptor gamma
Identification of Nogo-B as a new molecular target of peroxisome proliferator-activated receptor gamma
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鉴定 Nogo-B 作为过氧化物酶体增殖物激活受体 γ 的新分子靶标
DOI：
10.1016/j.cellsig.2019.109429
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发表时间：
2020
影响因子：
4.8
通讯作者：
Chen Yuanli
中科院分区：
文献类型：
--
作者：
Yu Miao;Zhang Shuang;Guo Fangling;Yang Xiaoxiao;Li Qi;Wei Zhuo;Han Jihong;Duan Yajun;Chen Yuanli
非酒精性脂肪性肝病（NAFLD）是一种全球范围内快速增长的慢性肝病，可导致肝硬化。过氧化物酶体增殖物激活受体γ（Peroxisome proliferator-activated receptor γ，PPARγ）是一种配体激活的转录因子，在脂肪生成中起重要作用。可以在肝硬化患者的肝脏中确定增加的Nogo-B表达。然而，PPARγ激活对肝脏Nogo-B表达的影响仍然未知。在这项研究中，我们发现罗格列酮或去磷酸化激活的PPARγ在mRNA和蛋白水平上增加了HepG 2细胞和小鼠原代肝细胞中Nogo-B的表达。此外，我们还在Nogo-B启动子中发现了一个PPRE，并发现PPRE依赖于PPRE的方式促进Nogo-B的转录。ChIP实验进一步证实罗格列酮增强了Nogo-B启动子与PPARγ的结合。我们使用肝脏特异性PPARγ缺陷小鼠，确定了PPARγ表达在调节肝脏Nogo-B表达中的关键作用。培养基中葡萄糖和棕榈酸盐的增加激活了小鼠原代肝细胞中Nogo-B和PPARγ的表达，相应的，高脂饮食（HFD）诱导的脂肪肝与小鼠肝脏Nogo-B和PPARγ表达的增加相关。类似地，NAFLD患者的血清Nogo-B水平升高。然而，罗格列酮治疗减少HFD诱导的脂肪肝和Nogo-B表达。总之，我们的研究确定Nogo-B是PPARγ的新分子靶点，并表明Nogo-B的增加可能是NAFLD的潜在指标。
Nonalcoholic fatty liver disease (NAFLD) is a fast-growing chronic liver disease worldwide which can lead to liver cirrhosis. Peroxisome proliferator-activated receptor γ (PPARγ), a ligand-activated transcription factor, plays an important role in lipogenesis. Increased Nogo-B expression can be determined in the liver of cirrhosis patients. However, the effect of PPARγ activation on hepatic Nogo-B expression remains unknown. In this study, we found PPARγ activation by rosiglitazone or dephosphorylation increased Nogo-B expression at mRNA and protein levels in HepG2 cells and mouse primary hepatocytes. Furthermore, we identified a PPARγ response element (PPRE) in Nogo-B promoter and found PPARγ enhanced Nogo-B transcription in a PPRE-dependent manner. ChIP assay further confirms rosiglitazone enhanced the binding of PPARγ to Nogo-B promoter. Using a liver specific PPARγ deficient mice, we determined the critical role of PPARγ expression in regulating hepatic Nogo-B expression. Increased glucose and palmitate in culture medium activated Nogo-B and PPARγ expression in mouse primary hepatocytes, and corresponding, high-fat diet (HFD) induced fatty liver associated with increased hepatic Nogo-B and PPARγ expression in mice. Similarly, serum Nogo-B levels in patients with NAFLD were increased. However, rosiglitazone treatment reduced HFD-induced fatty liver and Nogo-B expression. In summary, our study identifies Nogo-B as a new molecular target of PPARγ, and suggests increased Nogo-B might be a potential indicator for NAFLD.