SIRT3 is regulated by nutrient excess and modulates hepatic susceptibility to lipotoxicity.
SIRT3 is regulated by nutrient excess and modulates hepatic susceptibility to lipotoxicity.
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DOI：
10.1016/j.freeradbiomed.2010.07.009
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发表时间：
2010-10-15
影响因子：
7.4
通讯作者：
Sack, Michael N.
中科院分区：
文献类型：
--
作者：
Bao, Jianjun;Scott, Iain;Lu, Zhongping;Pang, Liyan;Dimond, Christopher C.;Gius, David;Sack, Michael N.
SIRT3是主要的线粒体脱乙酰酶，调节线粒体代谢和氧化应激调节途径。然而，它在应对营养过剩方面的作用仍不清楚。因此，我们研究了SIRT3对电子转移链的调节，并评价了SIRT3在肝脏脂毒应激中的作用。SIRT3缺失的HepG2细胞表现出线粒体电子传输链功能的弥漫性中断，线粒体膜电位的同时降低，以及过量的基础活性氧水平。由于这种表型可能易于增加脂肪毒性肝脏的易感性，我们评估了SIRT3在慢性高脂饮食后小鼠肝脏中的表达。在这个营养过剩的模型中，SIRT3转录和蛋白水平被下调，同时肝脏脂肪储存增加和氧化应激增加。用棕榈酸酯研究SIRT3基因敲除的小鼠原代肝细胞和SIRT3 siRNA耗竭的HepG2细胞对脂毒的敏感性。在SIRT3缺乏的条件下，棕榈酸酯增加了活性氧物种，增加了肝细胞的死亡。SIRT3水平的恢复和/或N-乙酰半胱氨酸的治疗可以缓解这些不良反应。总而言之，SIRT3起到了改善肝脏脂肪毒性的作用，尽管矛盾的是，暴露于高脂肪环境中会下调肝脏中这一适应性程序。这种依赖于SIRT3的脂毒敏感性可能部分地受到SIRT3介导的电子转移链流量控制的调节。
SIRT3 is the primary mitochondrial deacetylase that modulates mitochondrial metabolic and oxidative stress regulatory pathways. However, its role in response to nutrient excess remains unknown. Thus, we investigated SIRT3 regulation of the electron transfer chain and evaluated the role of SIRT3 in hepatic lipotoxic stress. SIRT3 depleted HepG2 cells shows diffuse disruption in mitochondrial electron transfer chain functioning, a concurrent reduction in the mitochondrial membrane potential, and excess basal reactive oxygen species levels. As this phenotype may predispose to increased lipotoxic hepatic susceptibility we evaluated the expression of SIRT3 in murine liver following chronic high-fat feeding. In this nutrient-excess model SIRT3 transcript and protein levels are downregulated in parallel with increased hepatic fat storage and oxidative stress. Palmitate was used to investigate lipotoxic susceptibility in SIRT3 knockout mouse primary hepatocytes and SIRT3 siRNA depleted HepG2 cells. Under SIRT3 deficient conditions palmitate enhances reactive oxygen species and increases hepatocyte cell death. Reconstitution of SIRT3 levels and/or treatment with N-acetylcysteine ameliorates these adverse effects. In conclusion SIRT3 functions to ameliorate hepatic lipotoxicity, although paradoxically, exposure to high-fat downregulates this adaptive program in the liver. This SIRT3-dependent lipotoxic susceptibility is possibly modulated, in part, by SIRT3 mediated control of electron transfer chain flux.
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影响因子：
7
作者：
Zhang, Junmei;Sprung, Robert;Zhao, Yingming
通讯作者：
Zhao, Yingming
影响因子：
14.8
作者：
Frezza, Christian;Cipolat, Sara;Scorrano, Luca
通讯作者：
Scorrano, Luca
影响因子：
4.8
作者：
Seifert, Erin L.;Estey, Carmen;Harper, Mary-Ellen
通讯作者：
Harper, Mary-Ellen
DOI：
10.1126/science.1179689
发表时间：
2010-02-19
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Zhao S;Xu W;Jiang W;Yu W;Lin Y;Zhang T;Yao J;Zhou L;Zeng Y;Li H;Li Y;Shi J;An W;Hancock SM;He F;Qin L;Chin J;Yang P;Chen X;Lei Q;Xiong Y;Guan KL
通讯作者：
Guan KL
影响因子：
5.6
作者：
Schlicker, Christine;Gertz, Melanie;Steegborn, Clemens
通讯作者：
Steegborn, Clemens