Center for Precision Medicine, Department of Internal Medicine, Section on Molecular Medicine, Wake Forest School of Medicine, Medical Center Boulevard, NRC, G-floor, NC, 27157, Winston-Salem, USA.
Department of Genetics, Texas Biomedical Research Institute, 78245, San Antonio, TX, USA.
BMC Genomics. 2021 Dec 3;22(1):870. doi: 10.1186/s12864-021-08166-0.
Dietary high fructose (HFr) is a known metabolic disruptor contributing to development of obesity and diabetes in Western societies. Initial molecular changes from exposure to HFr on liver metabolism may be essential to understand the perturbations leading to insulin resistance and abnormalities in lipid and carbohydrate metabolism. We studied vervet monkeys (Clorocebus aethiops sabaeus) fed a HFr (n=5) or chow diet (n=5) for 6 weeks, and obtained clinical measures of liver function, blood insulin, cholesterol and triglycerides. In addition, we performed untargeted global transcriptomics, proteomics, and metabolomics analyses on liver biopsies to determine the molecular impact of a HFr diet on coordinated pathways and networks that differed by diet.
We show that integration of omics data sets improved statistical significance for some pathways and networks, and decreased significance for others, suggesting that multiple omics datasets enhance confidence in relevant pathway and network identification. Specifically, we found that sirtuin signaling and a peroxisome proliferator activated receptor alpha (PPARA) regulatory network were significantly altered in hepatic response to HFr. Integration of metabolomics and miRNAs data further strengthened our findings.
Our integrated analysis of three types of omics data with pathway and regulatory network analysis demonstrates the usefulness of this approach for discovery of molecular networks central to a biological response. In addition, metabolites aspartic acid and docosahexaenoic acid (DHA), protein ATG3, and genes ATG7, and HMGCS2 link sirtuin signaling and the PPARA network suggesting molecular mechanisms for altered hepatic gluconeogenesis from consumption of a HFr diet.
饮食中的高果糖（HFr）是一种已知的代谢扰乱物，会导致西方社会肥胖和糖尿病的发生。暴露于 HFr 后对肝脏代谢的初始分子变化对于理解导致胰岛素抵抗和脂质及碳水化合物代谢异常的干扰可能是至关重要的。我们研究了喂食 HFr（n=5）或标准饮食（n=5）6 周的恒河猴（Clorocebus aethiops sabaeus），并获得了肝功能、血液胰岛素、胆固醇和甘油三酯的临床测量值。此外，我们对肝活检进行了非靶向的全球转录组学、蛋白质组学和代谢组学分析，以确定 HFr 饮食对不同饮食的协调途径和网络的分子影响。
我们表明，整合组学数据集提高了一些途径和网络的统计学意义，降低了其他途径和网络的统计学意义，这表明多个组学数据集增强了对相关途径和网络识别的信心。具体来说，我们发现，在肝脏对 HFr 的反应中，沉默信息调节因子信号和过氧化物酶体增殖物激活受体 alpha（PPARA）调节网络发生了显著改变。代谢组学和 miRNA 数据的整合进一步加强了我们的发现。
我们对三种类型的组学数据与途径和调控网络分析的综合分析表明，这种方法对于发现生物学反应的核心分子网络是有用的。此外，代谢物天冬氨酸和二十二碳六烯酸（DHA）、蛋白质 ATG3 以及基因 ATG7 和 HMGCS2 将沉默信息调节因子信号和 PPARA 网络联系起来，表明从 HFr 饮食中消耗导致肝糖异生改变的分子机制。
