Cardiovascular Branch, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Cells. 2021 Feb 22;10(2):467. doi: 10.3390/cells10020467.
Dietary supplementation is a widely adapted strategy to maintain nutritional balance for improving health and preventing chronic diseases. Conflicting results in studies of similar design, however, suggest that there is substantial heterogenicity in individuals' responses to nutrients, and personalized nutrition is required to achieve the maximum benefit of dietary supplementation. In recent years, nutrigenomics studies have been increasingly utilized to characterize the detailed genomic response to a specific nutrient, but it remains a daunting task to define the signatures responsible for interindividual variations to dietary supplements for tissues with limited accessibility. In this work, we used the hepatic response to omega-3 fatty acids as an example to probe such signatures. Through comprehensive analysis of nutrigenomic response to eicosapentaneoid acid (EPA) and/or docosahexaenoic acid (DHA) including both protein coding and long noncoding RNA (lncRNA) genes in human hepatocytes, we defined the EPA- and/or DHA-specific signature genes in hepatocytes. By analyzing gene expression variations in livers of healthy and relevant disease populations, we identified a set of protein coding and lncRNA signature genes whose responses to omega-3 fatty acid exhibit very high interindividual variabilities. The large variabilities of individual responses to omega-3 fatty acids were further validated in human hepatocytes from ten different donors. Finally, we profiled RNAs in exosomes isolated from the circulation of a liver-specific humanized mouse model, in which the humanized liver is the sole source of human RNAs, and confirmed the in vivo detectability of some signature genes, supporting their potential as biomarkers for nutrient response. Taken together, we have developed an efficient and practical procedure to identify nutrient-responsive gene signatures as well as accessible biomarkers for interindividual variations.
饮食补充是一种广泛采用的策略，旨在维持营养平衡，改善健康状况，预防慢性疾病。然而，设计相似的研究结果存在冲突，这表明个体对营养素的反应存在很大的异质性，需要个性化营养才能最大程度地受益于饮食补充。近年来，营养基因组学研究越来越多地用于描述对特定营养素的详细基因组反应，但对于有限可及组织中对饮食补充剂的个体间变异负责的特征仍然是一项艰巨的任务。在这项工作中，我们使用 omega-3 脂肪酸对肝脏的反应为例来探究这些特征。通过对人类肝细胞中二十碳五烯酸 (EPA) 和/或二十二碳六烯酸 (DHA) 的营养基因组反应进行全面分析，包括蛋白质编码和长非编码 RNA (lncRNA) 基因，我们定义了肝细胞中 EPA 和/或 DHA 特异性特征基因。通过分析健康和相关疾病人群肝脏中的基因表达变化，我们鉴定了一组蛋白质编码和 lncRNA 特征基因，其对 omega-3 脂肪酸的反应表现出非常高的个体间变异性。个体对 omega-3 脂肪酸的反应的大变异在来自十个不同供体的人类肝细胞中进一步得到了验证。最后，我们对来源于肝脏特异性人源化小鼠模型循环中分离的外泌体中的 RNA 进行了分析，在该模型中，人源化肝脏是人 RNA 的唯一来源，并证实了一些特征基因的体内可检测性，支持它们作为营养反应生物标志物的潜力。总之，我们已经开发出一种有效且实用的程序来鉴定营养反应基因特征以及个体间变异的可及生物标志物。
