Hauck Amy K, Zhou Tong, Upadhyay Ambuj, Sun Yuxiang, O'Connor Michael B, Chen Yue, Bernlohr David A
Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, MN 55455, USA.
Department of Molecular Biology, Cell Biology, Developmental Biology and Genetics, University of Minnesota, Minneapolis, MN 55455, USA.
Antioxidants (Basel). 2020 Dec 1;9(12):1210. doi: 10.3390/antiox9121210.
Oxidative stress is a hallmark of metabolic disease, though the mechanisms that define this link are not fully understood. Irreversible modification of proteins by reactive lipid aldehydes (protein carbonylation) is a major consequence of oxidative stress in adipose tissue and the substrates and specificity of this modification are largely unexplored. Here we show that histones are avidly modified by 4-hydroxynonenal (4-HNE) in vitro and in vivo. Carbonylation of histones by 4-HNE increased with age in male flies and visceral fat depots of mice and was potentiated in genetic (/) and high-fat feeding models of obesity. Proteomic evaluation of in vitro 4-HNE- modified histones led to the identification of both Michael and Schiff base adducts. In contrast, mapping of sites in vivo from obese mice exclusively revealed Michael adducts. In total, we identified 11 sites of 4-hydroxy hexenal (4-HHE) and 10 sites of 4-HNE histone modification in visceral adipose tissue. In summary, these results characterize adipose histone carbonylation as a redox-linked epigenomic mark associated with metabolic disease and aging.
氧化应激是代谢性疾病的一个标志，尽管确定这种联系的机制尚未完全了解。活性脂质醛对蛋白质的不可逆修饰（蛋白质羰基化）是脂肪组织氧化应激的主要后果，而这种修饰的底物和特异性在很大程度上尚未得到探索。在这里，我们表明组蛋白在体外和体内都被4-羟基壬烯醛（4-HNE）大量修饰。4-HNE导致的组蛋白羰基化在雄性果蝇和小鼠内脏脂肪库中随年龄增加，并且在肥胖的遗传（/）和高脂喂养模型中增强。对体外4-HNE修饰的组蛋白进行蛋白质组学评估，鉴定出了迈克尔加成物和席夫碱加成物。相比之下，对肥胖小鼠体内位点的定位仅揭示了迈克尔加成物。我们总共在内脏脂肪组织中鉴定出11个4-羟基己烯醛（4-HHE）修饰组蛋白的位点和10个4-HNE修饰组蛋白的位点。总之，这些结果将脂肪组蛋白羰基化表征为与代谢性疾病和衰老相关的氧化还原相关表观基因组标记。
