Identification of activation of tryptophan‐NAD+ pathway as a central metabolic response to chemical stress from feeding thermally‐oxidized soybean oil in mouse through metabolomics‐based biochemical analysis

Abstract

Consumption of thermally‐oxidized lipids is associated with metabolic disorders and cardiovascular disease. However, the specific metabolic events induced by thermally‐oxidized lipids and their underlying mechanisms are not well defined. In this study, the metabolic responses to consuming thermally‐oxidized vegetable oil were examined through metabolomics‐guided biochemical analysis. The control diet containing 7% (w/w) fresh soybean oil diet (CSO) and the treatment diet containing 7% (w/w) heated soybean oil (HSO) were fed to two groups of C57BL/6 mice for 4 weeks, respectively. Liquid chromatography‐mass spectrometry (LC‐MS)‐based metabolomic analysis indicated that HSO greatly altered the composition of metabolomes in serum, urine, and liver samples. A group of hydroxylalkenoic acids in urine were identified as newly formed metabolites from HSO treatment. HSO altered the lipidome, which was indicated by the increases of phospholipids containing saturated fatty acids and the decrease of phospholipids containing polyunsaturated fatty acids in the liver and serum. In the liver, HSO‐induced disruption of redox balance was reflected by the decrease of glutathione (GSH) and ascorbic acid and the upregulation of detoxifying gene expression. Moreover, the levels of several microbial metabolites in urine were affected by HSO, suggesting the changes in microflora. Above all, the most prominent metabolic changes induced by HSO occurred in the tryptophan‐NAD+ pathway since multiple metabolites in this pathway were affected, including the decrease of serum tryptophan, the increases of NAD+ and adenosine metabolites in the liver, and the increases of kynurenic acid, nicotinamide, and nicotinamide N‐oxide in urine. The activation of tryptophan‐NAD+ pathway was confirmed by observing the upregulation of tryptophan 2,3‐dioxygenase, kynureninase, and quinolinate phosphoribosyl transferase expression in this pathway, likely contributed by the activation of peroxisome proliferator‐activated receptor α (PPARα), as suggested by the upregulation of PPARα target genes in the liver and the decreases of triacylglycerols in both serum and liver. Since NAD+ and its metabolites are the indispensable cofactors or substrates of major metabolic events induced by HSO, including the detoxification of reactive aldehydes through aldehyde dehydrogenase, sustaining redox balance and DNA repair activities, and PPARα–mediated metabolic reactions, such as fatty acid β‐oxidation, the activation of tryptophan‐NAD+ pathway is deemed to be a central metabolic event induced by thermally‐oxidized lipids.Support or Funding InformationNIFA project MIN‐18‐092