Enhanced expression of Nrf2 in mice attenuates the fatty liver produced by a methionine- and choline-deficient diet.
Enhanced expression of Nrf2 in mice attenuates the fatty liver produced by a methionine- and choline-deficient diet.
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DOI：
10.1016/j.taap.2010.03.016
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发表时间：
2010-06-15
影响因子：
3.8
通讯作者：
Klaassen CD
中科院分区：
文献类型：
--
作者：
Zhang YK;Yeager RL;Tanaka Y;Klaassen CD
氧化应激已被认为是脂肪肝疾病进展的重要促进因素。目前的研究探讨了Nrf 2-Keap 1信号通路的潜在功能，一个重要的肝脏氧化应激传感器，在啮齿动物脂肪肝模型。对无Nrf 2表达（Nrf 2-null）、Nrf 2表达正常（野生型，WT）和Nrf 2表达增强（Keap 1敲低，K1-kd）的小鼠饲喂蛋氨酸和胆碱缺乏（MCD）饲料或对照饲料5天。与WT小鼠相比，MCD饲料引起的脂肪肝在Nrf 2缺失小鼠中更严重，在K1-kd小鼠中更轻。在喂食MCD饲料的三种基因型中，Nrf 2基因敲除小鼠的肝脏谷胱甘肽含量较低，脂质过氧化程度较高，而K1-kd小鼠的肝脏谷胱甘肽含量最高，脂质过氧化程度最低。MCD饲料激活了Nrf 2信号通路，WT小鼠中诱导了Nrf 2靶向细胞保护基因Nqo 1和Gstα1/2，K1-kd小鼠中诱导的细胞保护基因更多。此外，对照组和MCD饲料组的Nrf 2基因敲除小鼠均显示脂肪酸代谢基因的表达谱改变，表明Nrf 2可能影响肝脏中的脂质代谢。例如，与喂食MCD饲料的WT小鼠相比，Nrf 2缺失小鼠肝脏中长链脂肪酸移位酶CD 36和内分泌激素Fgf 21的mRNA水平较高，K1-kd小鼠肝脏中的mRNA水平较低。总之，这些观察结果表明，Nrf 2可通过增加肝脏抗氧化和解毒能力来减缓MCD饲料引起的脂肪肝发作。
Oxidative stress has been proposed as an important promoter of the progression of fatty liver diseases. The current study investigates the potential functions of the Nrf2–Keap1 signaling pathway, an important hepatic oxidative stress sensor, in a rodent fatty liver model. Mice with no (Nrf2-null), normal (wild type, WT), and enhanced (Keap1 knockdown, K1-kd) expression of Nrf2 were fed a methionine- and choline-deficient (MCD) diet or a control diet for 5 days. Compared to WT mice, the MCD diet-caused hepatosteatosis was more severe in the Nrf2-null mice and less in the K1-kd mice. The Nrf2-null mice had lower hepatic glutathione and exhibited more lipid peroxidation, whereas the K1-kd mice had the highest amount of glutathione in the liver and developed the least lipid peroxidation among the three genotypes fed the MCD diet. The Nrf2 signaling pathway was activated by the MCD diet, and the Nrf2-targeted cytoprotective genes Nqo1 and Gstα1/2 were induced in WT and even more in K1-kd mice. In addition, Nrf2-null mice on both control and MCD diets exhibited altered expression profiles of fatty acid metabolism genes, indicating Nrf2 may influence lipid metabolism in liver. For example, mRNA levels of long chain fatty acid translocase CD36 and the endocrine hormone Fgf21 were higher in livers of Nrf2-null mice and lower in the K1-kd mice than WT mice fed the MCD diet. Taken together, these observations indicate that Nrf2 could decelerate the onset of fatty livers caused by the MCD diet by increasing hepatic antioxidant and detoxification capabilities.
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DOI：
10.1016/j.jpba.2008.08.033
发表时间：
2008-12-15
影响因子：
3.4
作者：
Chen, Wei;Zhao, Yong;Seefeldt, Teresa;Guan, Xiangming
通讯作者：
Guan, Xiangming
影响因子：
3.9
作者：
Cheng, XG;Maher, J;Klaassen, CD
通讯作者：
Klaassen, CD
影响因子：
29.4
作者：
Lamle, Jutta;Marhenke, Silke;Vogel, Arndt
通讯作者：
Vogel, Arndt
影响因子：
15.9
作者：
Leclercq, IA;Farrell, GC;Robertson, GR
通讯作者：
Robertson, GR
DOI：
10.1006/bbrc.1997.6943
发表时间：
1997-07-18
影响因子：
3.1
作者：
Itoh, K;Chiba, T;Nabeshima, Y
通讯作者：
Nabeshima, Y