Effects of fasting and inflammatory challenges on the swine hepatic metabolome

The liver is simultaneously impacted by environmental challenges and modulates the response to these insults. Efforts to understand the effects of stressors on the activity of the liver typically consider one type of challenge (e.g., nutrition, toxin, disease), profile targeted molecules, or study the hepatic disruptions in one sex. The present study characterized hepatic changes in the metabolome of females and males exposed to the nutritional challenge of fasting and inflammatory signals elicited by the viral mimetic Poly(I:C). The hepatic metabolome of pigs was profiled using untargeted liquid chromatography-mass spectrometry analysis enabling the quantification of metabolites. The analysis of pathways enriched among metabolites showing sex-by-distress interactions revealed molecular processes affected by fasting and immune stresses in a sex-specific manner, including SLC-mediated transmembrane transport, the urea cycle, and G-protein coupled receptor signaling. Metabolites differentially abundant across sex-distress groups in the previous pathways included creatine, taurine, and glycine derivatives. Pathways over-represented among metabolites significantly affected by distress included glucose homeostasis, the Krebs cycle, and the metabolism of water-soluble vitamins, with key metabolites including S-adenosylmethionine, histidine, glycerophosphocholine, and lactic acid. These results indicate that 24-h fasting, and low-grade systemic inflammation modulate the liver metabolism. The detection of metabolic disruption that varies with sex enforces the need to develop therapies that can restore hepatic homeostasis in females and males.