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, HMGCS2 link sirtuin signaling and the PPARA network suggesting molecular mechanisms for altered hepatic gluconeogenesis from consumption of a HFr diet.

Multi-Omics Comparison of the Spontaneous Diabetes Mellitus and Diet-Induced Prediabetic Macaque Models

“…Macaques, including those in Macaca fascicularis, have contributed to the studies of DM for decades ( Yasuda et al, 1988 ; Hansen, 2010 ; Bauer et al, 2011 ; Harwood et al, 2012 ; Pound et al, 2014 ; Havel et al, 2017 ). Recently, other groups have also reported multi-omics datasets from monkeys of spontaneous type 2 DM ( Lei et al, 2020 ), and monkeys fed with a high-fructose diet ( Cox et al, 2021 ). Our work has added an additional database for scientists in the field.…”

“…The animals that developed diabetes mellitus spontaneously provided important insights into the molecular and cellular pathology of DM ( Yasuda et al, 1988 ; Bauer et al, 2011 ; Harwood et al, 2012 ; Wang et al, 2013 ). Because animals of other orders do not fully recapitulate metabolic changes of primates, non-human primates (NHPs) are of value in DM study with genetic and physiological similarity to humans ( Yasuda et al, 1988 ; Hansen, 2010 ; Bauer et al, 2011 ; Harwood et al, 2012 ; Pound et al, 2014 ; Havel et al, 2017 ; Lei et al, 2020 ; Cox et al, 2021 ). With the datasets representing the cellular and molecular alterations at various levels in NHPs of spontaneous DM (sDM), researchers can project the data from clinical and experimental studies to the picture of the correlated metabolic and gene expression profiles.…”