Integrated omics analysis reveals sirtuin signaling is central to hepatic response to a high fructose diet

Abstract

Background 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. Results 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. Conclusions 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.

Integrated multi-omics analysis of brain aging in female nonhuman primates reveals altered signaling pathways relevant to age-related disorders

“…In addition, previous studies used only RNA-Seq data to quantify molecular changes; whereas, this study integrated transcriptomic, proteomic, and metabolomic data. In previous studies, we (Cox et al, 2021) and others (e.g., (Meng et al, 2019) have demonstrated greater power to detect phenotypically relevant molecular pathways using integrated omics compared to transcriptomics analyses alone.…”

GM-CSF disruption in CART cells modulates T cell activation and enhances CART cell anti-tumor activity

“…Despite the remarkable activity of CD19-directed chimeric antigen receptor T cell (CART19) therapy in treating B-cell hematologic malignancies, 1 , 2 limitations include 1) the development of potential life-threatening complications such as neurotoxicity (NT) and cytokine release syndrome (CRS) 3 , 4 and 2) lack of durable response. 5 – 8 Emerging literature suggests that inhibitory myeloid cells and their cytokines play an important role in inducing CART cell toxicities and contribute to CART inhibition. 9 – 12 Specifically, and of relevance to the work presented in this manuscript, granulocyte-macrophage colony-stimulating factor (GM-CSF) is implicated in the development of NT and CRS after CART19 therapy based on correlative studies from pivotal clinical trials.…”