Homocysteine activates autophagy by inhibition of CFTR expression via interaction between DNA methylation and H3K27me3 in mouse liver.
Homocysteine activates autophagy by inhibition of CFTR expression via interaction between DNA methylation and H3K27me3 in mouse liver.
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同型半胱氨酸通过小鼠肝脏中 DNA 甲基化和 H3K27me3 之间的相互作用抑制 CFTR 表达来激活自噬
DOI：
10.1038/s41419-017-0216-z
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发表时间：
2018-02-07
影响因子：
9
通讯作者：
Jiang Y
中科院分区：
文献类型：
--
作者：
Yang A;Jiao Y;Yang S;Deng M;Yang X;Mao C;Sun Y;Ding N;Li N;Zhang M;Jin S;Zhang H;Jiang Y
据报道，高同型半胱氨酸（Hcy）水平升高与肝损伤有关，自噬在正常肝脏生理和病理生理中起重要作用，但Hcy调节自噬的机制目前尚不清楚。本研究采用常规饮食喂养CBS+/-小鼠12周建立高同型半胱氨酸血症（HHcy）模型，并用Hcy处理HL-7702细胞，我们发现Hcy通过下调囊性纤维化跨膜传导调节剂（CFTR）在体内和体外的表达，增加自噬，加重肝损伤。CFTR的过表达抑制了自噬体的形成和自噬相关蛋白BECN1、LC3-II/I和Atg12的表达，而在hcy处理的肝细胞和注射了表达CFTR的慢病毒的CBS+/-小鼠中，p62的表达增加。进一步研究表明，CFTR的表达受DNA甲基转移酶1 （DNMT1）和zeste同源物增强子2 （EZH2）的相互作用调控，它们分别调控DNA甲基化和组蛋白H3赖氨酸27三甲基化（H3K27me3）。综上所述，我们的研究表明Hcy在小鼠肝脏中通过H3K27me3与DNA甲基化的相互作用抑制CFTR的表达，从而激活自噬。这些发现为hcy诱导的自噬在肝损伤中的机制提供了新的见解。
Elevated homocysteine (Hcy) levels have been reported to be involved in liver injury, and autophagy plays an important role in normal hepatic physiology and pathophysiology, but the mechanism underlying Hcy regulated autophagy is currently unknown. In this study, CBS+/- mice were fed with regular diet for 12 weeks to establish a hyperhomocysteinemia (HHcy) model and HL-7702 cells were treated with Hcy, we found that Hcy increases autophagy and aggravates liver injury by downregulation of cystic fibrosis transmembrane conductance regulator (CFTR) expression in vivo and in vitro. Overexpression of CFTR inhibited the formation of autophagosomes and the expression of autophagy-related proteins BECN1, LC3-II/I and Atg12, while the expression of p62 increased in Hcy-treated hepatocytes and CBS+/- mice injected with lentivirus expressing CFTR. Further study showed that CFTR expression is regulated by the interaction of DNA methyltransferase 1 (DNMT1) and enhancer of zeste homolog 2 (EZH2), which, respectively, regulate DNA methylation and histone H3 lysine 27 trimethylation (H3K27me3). In conclusion, our study showed that Hcy activates autophagy by inhibition of CFTR expression via interaction between H3K27me3 and DNA methylation in the mouse liver. These findings provide new insight into the mechanism of Hcy-induced autophagy in liver injury.
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DOI：
10.1002/hep.28138
发表时间：
2015-12
期刊：
Hepatology (Baltimore, Md.)
影响因子：
--
作者：
Spirli C;Villani A;Mariotti V;Fabris L;Fiorotto R;Strazzabosco M
通讯作者：
Strazzabosco M
影响因子：
17.1
作者：
Bayliss J;Mukherjee P;Lu C;Jain SU;Chung C;Martinez D;Sabari B;Margol AS;Panwalkar P;Parolia A;Pekmezci M;McEachin RC;Cieslik M;Tamrazi B;Garcia BA;La Rocca G;Santi M;Lewis PW;Hawkins C;Melnick A;David Allis C;Thompson CB;Chinnaiyan AM;Judkins AR;Venneti S
通讯作者：
Venneti S
DOI：
10.1007/s12031-011-9695-z
发表时间：
2012-05
期刊：
Journal of molecular neuroscience : MN
影响因子：
--
作者：
Tyagi N;Qipshidze N;Munjal C;Vacek JC;Metreveli N;Givvimani S;Tyagi SC
通讯作者：
Tyagi SC
影响因子：
5.6
作者：
Kim, Ji-Myung;Hong, Kyungju;Chang, Namsoo
通讯作者：
Chang, Namsoo
影响因子：
3.8
作者：
Jacobs, Rene L.;Jiang, Hua;Maclean, Kenneth N.
通讯作者：
Maclean, Kenneth N.