Distinct role of nuclear receptor corepressor 1 regulated de novo fatty acids synthesis in liver regeneration and hepatocarcinogenesis in mice.
Distinct role of nuclear receptor corepressor 1 regulated de novo fatty acids synthesis in liver regeneration and hepatocarcinogenesis in mice.
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核受体辅阻遏物1调节脂肪酸从头合成在小鼠肝再生和肝癌发生中的独特作用
DOI：
10.1002/hep.29562
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发表时间：
2018-03
期刊：
影响因子：
--
通讯作者：
Chen L
中科院分区：
文献类型：
--
作者：
Ou-Yang Q;Lin XM;Zhu YJ;Zheng B;Li L;Yang YC;Hou GJ;Chen X;Luo GJ;Huo F;Leng QB;Gonzalez FJ;Jiang XQ;Wang HY;Chen L
当务之急是找到改善肝脏再生(LR)的方法，同时降低同时发生肝癌(HCG)的风险。核受体辅阻遏子1(NCoR1)是核受体的辅阻遏子，调节代谢基因的表达水平，但其对LR和HCG的潜在作用却知之甚少。在这里，我们发现小鼠的肝脏特异性NCoR1HEP(NCoR1HEP)显著增强了部分肝切除后的LR，令人惊讶的是，它阻断了二乙基亚硝胺(DEN)诱导的Δ的过程。核糖核酸测序和代谢分析结果均显示，在NCoR1HeP小鼠中FASN和Acc2的表达增强，这表明从头合成脂肪酸(Fas)在LR中起着关键作用。NCoR1HEP小鼠体内Fas的持续增强导致三磷酸腺苷和烟酰胺腺嘌呤二核苷酸磷酸(NADPH)的消耗超负荷，线粒体活性氧产生增加，从而在DEN给药后早期诱导肝细胞凋亡，从而抑制Δ。结论：NCOR1是肝脏Fas和线粒体能量适应的负性调节因子，在肝再生和癌变过程中发挥着不同的作用。
It is urgent that the means to improve liver regeneration (LR) be found, while mitigating the concurrent risk of hepatocarcinogenesis (HCG). Nuclear receptor corepressor 1 (NCoR1) is a co-repressor of nuclear receptors, which regulates the expression level of metabolic genes; however, little is known about its potential contribution for LR and HCG. Here, we found that liver-specific NCoR1 knockout in mice (NCoR1Δhep) dramatically enhances LR after partial hepatectomy and, surprisingly, blocks the process of diethylnitrosamine (DEN)-induced HCG. Both RNA-sequencing and metabolic assay results revealed improved expression of Fasn and Acc2 in NCoR1Δhep mice, suggesting the critical role of de novo fatty acid synthesis (FAS) in LR. Continual enhanced de novo FAS in NCoR1Δhep mice resulted in overwhelmed adenosine triphosphate ATP and nicotinamide adenine dinucleotide phosphate (NADPH) consumption and increased mitochondrial reactive oxygen species production, which subsequently attenuated HCG through inducing apoptosis of hepatocytes at an early stage after DEN administration. Conclusion: NCoR1 functions as a negative modulator for hepatic de novo FAS and mitochondria energy adaptation, playing distinct roles in regeneration or carcinogenesis.
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影响因子：
64.8
作者：
Alenghat, Theresa;Meyers, Katherine;Mullican, Shannon E.;Leitner, Kirstin;Adeniji-Adele, Adetoun;Avila, Jacqueline;Bucan, Maja;Ahima, Rexford S.;Kaestner, Klaus H.;Lazar, Mitchell A.
通讯作者：
Lazar, Mitchell A.
影响因子：
13.5
作者：
Zhang, Lisheng;Wang, Yan-Dong;Chen, Wei-Dong;Wang, Xichun;Lou, Guiyu;Liu, Nian;Lin, Min;Forman, Barry M.;Huang, Wendong
通讯作者：
Huang, Wendong
影响因子：
25.7
作者：
Kohjima, Motoyuki;Tsai, Tsung-Huang;Tackett, Bryan C.;Thevananther, Sundararajah;Li, Lan;Chang, Benny Hung-Junn;Chan, Lawrence
通讯作者：
Chan, Lawrence
影响因子：
29.4
作者：
Malato, Yann;Ehedego, Haksier;Trautwein, Christian
通讯作者：
Trautwein, Christian
NCOR1是肌肉质量和氧化功能的保守生理调节剂。
影响因子：
64.5
作者：
Yamamoto H;Williams EG;Mouchiroud L;Cantó C;Fan W;Downes M;Héligon C;Barish GD;Desvergne B;Evans RM;Schoonjans K;Auwerx J
通讯作者：
Auwerx J