Nutritional stress exacerbates hepatic steatosis induced by deletion of the histidine nucleotide-binding (Hint2) mitochondrial protein
Nutritional stress exacerbates hepatic steatosis induced by deletion of the histidine nucleotide-binding (Hint2) mitochondrial protein
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DOI：
10.1152/ajpgi.00178.2015
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发表时间：
2016-04-01
影响因子：
4.5
通讯作者：
St-Pierre, Marie V.
中科院分区：
文献类型：
--
作者：
Martin, Juliette;Balmer, Maria L.;St-Pierre, Marie V.
组氨酸核苷酸结合蛋白Hint 2是一种线粒体磷酰胺酶，在肝脏、棕色脂肪、胰腺和肌肉中表达。Hint 2基因敲除（Hint 2（-/-））小鼠的肝脏积累甘油三酯，并显示线粒体蛋白赖氨酸乙酰化的模式。赖氨酸乙酰化变化的程度和性质以及Hint 2（-/-）小鼠对引起蛋白质乙酰化修饰的营养挑战的反应尚未研究。为了比较Hint 2（-/-）和对照（Hint 2（-/-））小鼠对禁食和高脂饮食（HFD）的适应性，我们使动物自由进食或禁食24小时，并使动物接受HFD或对照饮食8周。Hint 2（-/-）肝脏中的甘油三酯含量高于Hint 2（-/-）肝脏，而血浆甘油三酯低四倍。丙二酰辅酶A水平在Hint 2（-/-）肝脏中增加了两倍。禁食24小时后，Hint 2（-/-）显示体温下降，与棕色脂肪质量下降和解偶联蛋白1下调相当。HFD处理的Hint 2（-/-）肝脏显示出更多的脂肪变性，血浆胰岛素和胆固醇高于Hint（-/-）小鼠。几种蛋白质被鉴定为sirtuin 3和5的底物，并在中间体和酮代谢中具有活性，在HFD和禁食方案后，肝脏和棕色脂肪线粒体中被乙酰化。谷氨酸脱氢酶活性在进食和禁食的肝脏下调，这是由于乙酰化和ADP-核糖基化的增加。Hint 2的缺乏使几种线粒体蛋白的翻译后修饰失调，这阻碍了对营养应激事件的适应。
The histidine nucleotide-binding protein, Hint2, is a mitochondrial phosphoramidase expressed in liver, brown fat, pancreas, and muscle. The livers of Hint2 knockout (Hint2(-/-)) mice accumulate triglycerides and show a pattern of mitochondrial protein lysine hyperacetylation. The extent and nature of the lysine acetylation changes and the response of Hint2(-/-) mice to nutritional challenges that elicit a modification of protein acetylation have not been investigated. To compare the adaptation of Hint2(-/-) and control (Hint2(-/-)) mice with episodes of fasting and high-fat diet (HFD), we subjected animals to either feeding ad libitum or fasting for 24 h, and to either a HFD or control diet for 8 wk. Triglyceride content was higher in Hint2(-/-) than in Hint2(-/-) livers, whereas plasma triglycerides were fourfold lower. Malonyl-CoA levels were increased twofold in Hint2(-/-) livers. After 24 h fasting, Hint2(-/-) displayed a decrease in body temperature, commensurate with a decrease in mass of brown fat and downregulation of uncoupling protein 1. HFD-treated Hint2(-/-) livers showed more steatosis, and plasma insulin and cholesterol were higher than in Hint(-/-) mice. Several proteins identified as substrates of sirtuin 3 and 5 and active in intermediary and ketone metabolism were hyperacetylated in liver and brown fat mitochondria after both HFD and fasting regimens. Glutamate dehydrogenase activity was downregulated in fed and fasted livers, and this was attributed to an increase in acetylation and ADP-ribosylation. The absence of Hint2 deregulates the posttranslational modification of several mitochondrial proteins, which impedes the adaptation to episodes of nutritional stress.