Metabolomic and transcriptomic analyses ofFmo5-/-mice reveal roles for flavin-containing monooxygenase 5 (FMO5) in NRF2-mediated oxidative stress, the unfolded protein response, lipid homeostasis, and carbohydrate and one-carbon metabolism

Abstract

AbstractFlavin-containing monooxygenase 5 (FMO5) is a member of the FMO family of proteins best known for their roles in the detoxification of foreign chemicals and more recently in endogenous metabolism. We have previously shown thatFmo5-/-mice display an age-related lean phenotype, with much reduced weight gain from 20 weeks of age. The phenotype is characterized by decreased fat deposition, lower plasma concentrations of glucose and cholesterol, higher glucose tolerance and insulin sensitivity, and resistance to diet-induced obesity. In the present study we report the use of metabolomic and transcriptomic analyses of livers ofFmo5-/-and wild-type mice to identify factors underlying the lean phenotype ofFmo5-/-mice and gain insights into the function of FMO5. Disruption of theFmo5gene has wide-ranging effects on the abundance of metabolites and expression of genes in the liver. The results reveal that FMO5 is involved in upregulating the NRF2-mediated oxidative stress response, the unfolded protein response and response to hypoxia and cellular stress, indicating a role for the enzyme in adaptation to oxidative and metabolic stress. FMO5 also plays a role in stimulating a wide range of metabolic pathways and processes, particularly ones involved in the regulation of lipid homeostasis, the uptake and metabolism of glucose, the generation of cytosolic NADPH, and in one-carbon metabolism. The results predict that FMO5 acts by stimulating the NRF2, XBP1, PPARA and PPARG regulatory pathways, while inhibiting STAT1 and IRF7 pathways.