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

Laura A Cox,Vivek Das,Prahlad Rao,Ellen Quillen,Michael Olivier,Genesio M Karere,Zeeshan Hamid,Jeannie Chan,Kylie Kavanagh,Avinash Jadhav,Jeremy P Glenn

doi:10.1186/s12864-021-08166-0

Abstract

BackgroundDietary 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.ResultsWe 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.ConclusionsOur 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.

Highlights

Dietary high fructose (HFr) is a known metabolic disruptor contributing to development of obesity and diabetes in Western societies
In cynomolgus monkeys (Macaca fascicularis), long-term exposure to high fructose (HFr) diets increased liver steatosis, with extent related to duration of fructose exposure [10], but questions remain about the initial molecular changes induced by high levels of fructose that result in long-term health complications
Total plasma cholesterol was increased, and measures of liver injury, alanine aminotransferase, alkaline phosphatase, and gamma-glutamyl transpeptidase were increased in animals fed the HFr diet compared to controls (Table 1)

Summary

Introduction

Dietary high fructose (HFr) is a known metabolic disruptor contributing to development of obesity and diabetes in Western societies. The vervet monkey (Chlorocebus aethiops sabaeus) is a model for multiple human complex diseases including neurodegenerative disease [11], Alzheimer’s disease [12,13,14,15], diabetes, obesity and metabolism [16,17,18] and cardiovascular disease [19, 20] among others. Studies in vervets related to metabolism have included diet interventions with variation in sources of protein, fat, and carbohydrate [18, 24, 25]; none of these studies in humans or NHP have used global untargeted omics approaches to identify potential molecular mechanisms underlying diet-induced changes in liver metabolism. No studies to date have generated an integrated comprehensive multi-omics dataset to better understand these molecular changes [26]

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Discussion

Conclusion