SIRT4 KO livers microarray

Sirtuins are a family of protein deacetylases, deacylases, and ADP-ribosyltransferases that regulate life span, control the onset of numerous age-associated diseases, and mediate metabolic homeostasis. We have uncovered a novel role for the mitochondrial sirtuin SIRT4 in the regulation of hepatic lipid metabolism during changes in nutrient availability. We show that SIRT4 levels decrease in the liver during fasting and that SIRT4 null mice display increased expression of hepatic peroxisome proliferator activated receptor (PPAR ) target genes associated with fatty acid catabolism. Accordingly, primary hepatocytes from SIRT4 knockout (KO) mice exhibit higher rates of fatty acid oxidation than wild-type hepatocytes, and SIRT4 overexpression decreases fatty acid oxidation rates. The enhanced fatty acid oxidation observed in SIRT4 KO hepatocytes requires functional SIRT1, demonstrating a clear cross talk between mitochondrial and nuclear sirtuins. Thus, SIRT4 is a new component of mitochondrial signaling in the liver and functions as an important regulator of lipid metabolism. SIRT4 knockout (KO) and wild-type (WT) littermates (male; n 6 per genotype; 7- to 8-month-old littermates) were sacrificed after a 16-h overnight fast. Samples were individually hybridized on Affymetrix Mouse Genome 430 2.0 GeneChips by the Biopolymers Facility (Harvard Medical School).沉默信息调节蛋白家族（Sirtuins）是一类兼具蛋白去乙酰化酶、去酰化酶及ADP核糖基转移酶活性的蛋白家族，可调控生物体寿命、控制众多年龄相关性疾病的发病进程，并介导代谢稳态维持。本研究首次揭示了线粒体沉默信息调节蛋白4（SIRT4）在营养供给状态改变时调控肝脏脂质代谢的全新功能。研究结果显示：禁食条件下小鼠肝脏内SIRT4的表达水平显著下调；SIRT4敲除（knockout, KO）小鼠的肝脏中，与脂肪酸分解代谢相关的过氧化物酶体增殖物激活受体（peroxisome proliferator activated receptor, PPAR）靶基因表达水平升高。相应地，源自SIRT4敲除（KO）小鼠的原代肝细胞，其脂肪酸氧化速率较野生型（wild-type, WT）肝细胞更高；而SIRT4过表达则会降低脂肪酸氧化速率。在SIRT4敲除肝细胞中观察到的脂肪酸氧化增强现象，依赖于具有功能活性的沉默信息调节蛋白1（SIRT1），这表明线粒体与细胞核内的sirtuin蛋白间存在明确的信号串扰。综上，SIRT4是肝脏线粒体信号通路的新型调控组分，可作为脂质代谢的重要调节因子发挥功能。本研究使用SIRT4敲除（KO）小鼠及其同窝野生型（WT）雄性小鼠（每个基因型组n=6，月龄为7~8个月），在禁食16小时后实施安乐死。样本由哈佛医学院生物聚合物平台（Biopolymers Facility, Harvard Medical School）分别在Affymetrix小鼠基因组430 2.0基因芯片（Affymetrix Mouse Genome 430 2.0 GeneChips）上完成杂交检测。