The histone demethylase Phf2 acts as a molecular checkpoint to prevent NAFLD progression during obesity.
The histone demethylase Phf2 acts as a molecular checkpoint to prevent NAFLD progression during obesity.
复制标题
DOI：
10.1038/s41467-018-04361-y
复制
发表时间：
2018-05-29
影响因子：
16.6
通讯作者：
Dentin R
中科院分区：
文献类型：
--
作者：
Bricambert J;Alves-Guerra MC;Esteves P;Prip-Buus C;Bertrand-Michel J;Guillou H;Chang CJ;Vander Wal MN;Canonne-Hergaux F;Mathurin P;Raverdy V;Pattou F;Girard J;Postic C;Dentin R
据报道，异常的组蛋白甲基化谱与肥胖期间NAFLD的发生和进展相关。然而，在这一过程中所涉及的特定表观遗传修饰剂的识别仍然知之甚少。在这里，我们确定组蛋白去甲基化酶植物同源结构域指2（Phf 2）作为一个新的转录因子碳水化合物反应元件结合蛋白（ChREBP）的转录共激活因子。通过特异性擦除ChREBP调节基因启动子上的H3 K9 me 2甲基标记，Phf 2促进代谢前体掺入单不饱和脂肪酸，导致在没有炎症和胰岛素抵抗的情况下发生脂肪肝。此外，Phf 2介导的转录因子NF-E2相关因子2（Nrf 2）的激活进一步将葡萄糖通量重新导向磷酸戊糖途径和谷胱甘肽生物合成，保护肝脏免受饮食诱导的肥胖症引起的氧化应激和纤维化。总的来说，我们的研究结果建立了一个下游表观遗传检查点，Phf 2通过促进特定基因启动子处的H3 K9 me 2去甲基化，保护肝脏免受NAFLD发病机制的影响。脂肪变性的特征在于脂质的初始积累，随后是炎症和最终的纤维化。在这里，作者表明组蛋白去甲基化酶植物同源结构域指2通过充当ChREBP的共激活剂来保护肝脏免受脂肪变性进展，因此，有利于脂质积聚而没有炎症。
Aberrant histone methylation profile is reported to correlate with the development and progression of NAFLD during obesity. However, the identification of specific epigenetic modifiers involved in this process remains poorly understood. Here, we identify the histone demethylase Plant Homeodomain Finger 2 (Phf2) as a new transcriptional co-activator of the transcription factor Carbohydrate Responsive Element Binding Protein (ChREBP). By specifically erasing H3K9me2 methyl-marks on the promoter of ChREBP-regulated genes, Phf2 facilitates incorporation of metabolic precursors into mono-unsaturated fatty acids, leading to hepatosteatosis development in the absence of inflammation and insulin resistance. Moreover, the Phf2-mediated activation of the transcription factor NF-E2-related factor 2 (Nrf2) further reroutes glucose fluxes toward the pentose phosphate pathway and glutathione biosynthesis, protecting the liver from oxidative stress and fibrogenesis in response to diet-induced obesity. Overall, our findings establish a downstream epigenetic checkpoint, whereby Phf2, through facilitating H3K9me2 demethylation at specific gene promoters, protects liver from the pathogenesis progression of NAFLD. Steatosis is characterized by initial accumulation of lipids, followed by inflammation and ultimately fibrosis. Here the authors show that the histone demethylase Plant Homeodomain Finger 2 protects liver form steatosis progression by acting as a co-activator of ChREBP, thus, favouring lipid accumulation without inflammation.
登录
查看更多内容
影响因子：
64.5
作者：
Kaelin WG Jr;McKnight SL
通讯作者：
McKnight SL
影响因子：
25.7
作者：
Akazawa Y;Cazanave S;Mott JL;Elmi N;Bronk SF;Kohno S;Charlton MR;Gores GJ
通讯作者：
Gores GJ
人类脂肪肝病：旧问题和新见解。
DOI：
10.1126/science.1204265
发表时间：
2011-06-24
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Cohen JC;Horton JD;Hobbs HH
通讯作者：
Hobbs HH
影响因子：
3.7
作者：
Fortschegger K;Shiekhattar R
通讯作者：
Shiekhattar R
DOI：
10.1074/jbc.m110.126870
发表时间：
2010-07-16
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
Ariyama H;Kono N;Matsuda S;Inoue T;Arai H
通讯作者：
Arai H