Martin Juliette, Balmer Maria L, Rajendran Saranya, Maurhofer Olivier, Dufour Jean-François, St-Pierre Marie V
Department of Clinical Research, University of Bern, Bern, Switzerland; and Department of Hepatology, Gastroenterology; and.
Department of Clinical Research, University of Bern, Bern, Switzerland; and Department of Hepatology, Gastroenterology; and Visceral Surgery, University Hospital, Inselspital, Bern, Switzerland
Am J Physiol Gastrointest Liver Physiol. 2016 Apr 1;310(7):G497-509. doi: 10.1152/ajpgi.00178.2015. Epub 2016 Jan 14.
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.
组氨酸核苷酸结合蛋白Hint2是一种在肝脏、棕色脂肪、胰腺和肌肉中表达的线粒体磷酸酰胺酶。Hint2基因敲除（Hint2(-/-)）小鼠的肝脏中甘油三酯积累，并呈现出线粒体蛋白赖氨酸超乙酰化模式。赖氨酸乙酰化变化的程度和性质，以及Hint2(-/-)小鼠对引发蛋白质乙酰化修饰的营养挑战的反应尚未得到研究。为了比较Hint2(-/-)小鼠和对照（Hint2(+/+)）小鼠在禁食和高脂饮食（HFD）情况下的适应性，我们让动物自由进食或禁食24小时，并给予HFD或对照饮食8周。Hint2(-/-)小鼠肝脏中的甘油三酯含量高于Hint2(+/+)小鼠，而血浆甘油三酯则低四倍。Hint2(-/-)小鼠肝脏中的丙二酰辅酶A水平增加了两倍。禁食24小时后，Hint2(-/-)小鼠的体温下降，这与棕色脂肪量的减少和解偶联蛋白1的下调相一致。接受HFD处理的Hint2(-/-)小鼠肝脏显示出更多的脂肪变性，血浆胰岛素和胆固醇水平高于Hint(+/+)小鼠。在HFD和禁食方案后，肝脏和棕色脂肪线粒体中几种被鉴定为沉默调节蛋白3和5的底物并在中间代谢和酮代谢中起作用的蛋白质发生了超乙酰化。喂食和禁食的肝脏中谷氨酸脱氢酶活性下调，这归因于乙酰化和ADP核糖基化的增加。Hint2的缺失会使几种线粒体蛋白的翻译后修饰失调，从而阻碍对营养应激情况的适应。
