Sirtuin 3 acts as a negative regulator of autophagy dictating hepatocyte susceptibility to lipotoxicity.
Sirtuin 3 acts as a negative regulator of autophagy dictating hepatocyte susceptibility to lipotoxicity.
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Sirtuin 3 作为自噬的负调节因子，决定肝细胞对脂毒性的敏感性
DOI：
10.1002/hep.29229
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发表时间：
2017-09
期刊：
影响因子：
--
通讯作者：
Song Z
中科院分区：
文献类型：
--
作者：
Li S;Dou X;Ning H;Song Q;Wei W;Zhang X;Shen C;Li J;Sun C;Song Z
饱和脂肪酸的脂毒性在非酒精性脂肪性肝病的发病机制中起着核心作用，但其确切机制(S)仍未完全阐明。SIRT3是一种依赖NAD+的脱乙酰酶，主要位于线粒体内。在这项研究中，我们证明了富含脂肪酸的高脂饮食(HFD)比等卡路里的不饱和脂肪酸高脂饮食(HFD)对肝脏的损害更大。出乎意料的是，在暴露于富含SFAs的HFD的小鼠肝脏中，SIRT3的表达/活性显著升高。利用培养的HepG2和AML-12肝细胞，我们证明了与单一不饱和脂肪酸不同，SFA上调了SIRT3的表达/活性。SIRT3过表达使肝脏和肝细胞都容易受到棕榈酸酯诱导的细胞死亡，这可以通过SIRT3 siRNA转基因来缓解。相反，抑制SIRT3可保护肝细胞免受棕榈酸酯的细胞毒性。进一步的研究表明，SIRT3作为自噬的负调控因子，从而增强了肝细胞对SFAs诱导的细胞毒性的敏感性。机制研究表明，SIRT3过表达导致锰超氧化物歧化酶(MnSOD)去乙酰化/激活，从而耗尽细胞内超氧化物歧化含量，导致AMP激活的蛋白激酶(AMPK)抑制和mTORC1激活，从而抑制自噬。相反，SIRT3 siRNA基因沉默增强了自噬通量。在SIRT3基因敲除小鼠的肝组织中也观察到了类似的结果。我们的研究证实SIRT3是一种新的自噬负调控因子，SFAs激活SIRT3可导致肝细胞的脂毒性，提示抑制SIRT3的过度激活可能成为治疗NAFLD和其他代谢疾病的一种潜在的治疗选择，而脂毒性是主要的发病机制。
Lipotoxicity induced by saturated fatty acids (SFAs) plays a central role in the pathogenesis of non-alcoholic fatty liver disease (NAFLD); however, the exact mechanism(s) remain to be fully elucidated. SIRT3 is an NAD+-dependent deacetylase primarily located inside mitochondria. In this study, we demonstrated that a SFAs-rich high-fat diet (HFD) was more detrimental to the liver than an isocaloric unsaturated FAs-rich HFD. Unexpectedly, SIRT3 expression/activity were significantly elevated in the livers of mice exposed to the SFAs-rich HFD. Using cultured HepG2 and AML-12 hepatocytes, we demonstrated that unlike monounsaturated FAs, SFAs upregulates SIRT3 expression/activity. SIRT3 overexpression renders both the liver and hepatocytes susceptible to palmitate-induced cell death, which can be alleviated by SIRT3 siRNA transfection. In contrast, SIRT3 suppression protects hepatocytes from palmitate cytotoxicity. Further studies revealed that SIRT3 acts as a negative regulator of autophagy, whereby enhancing the susceptibility of hepatocytes to SFAs-induced cytotoxicity. Mechanistic investigations elucidate that SIRT3 overexpression causes manganese superoxide dismutase (MnSOD) deacetylation/activation, which depleted intracellular superoxide contents, leading to AMP-activated protein kinase (AMPK) inhibition and mTORC1 activation, resulting in autophagy suppression. In contrast, SIRT3 siRNA gene silencing enhances autophagy flux. The similar result was observed in the liver tissue from SIRT3 knockout mice. our data identified SIRT3 to be a novel negative regulator of autophagy, whose activation by SFAs contributes to lipotoxicity in hepatocytes and suggest that restraining SIRT3 overactivation can be a potential therapeutic choice for the treatment of NAFLD as well as other metabolic disorders, with lipotoxicity being the principal pathomechanism.
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DOI：
10.1016/j.bbalip.2013.09.004
发表时间：
2014-01
期刊：
Biochimica et biophysica acta
影响因子：
--
作者：
Li S;Li J;Shen C;Zhang X;Sun S;Cho M;Sun C;Song Z
通讯作者：
Song Z
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作者：
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通讯作者：
Gores, GJ
影响因子：
4.8
作者：
Choi, Sung-E;Lee, Sung-Mi;Kang, Yup
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Kang, Yup
影响因子：
7.7
作者：
Lu, Zhongping;Bourdi, Mohammed;Sack, Michael N.
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