The global effect of naturally occurring metabolic cofactor supplementation
The prevalence of non-alcoholic fatty liver disease (NAFLD) continues to increase dramatically and there is no approved medication for its treatment. Recently, we revealed the underlying molecular mechanisms involved in the progression of NAFLD using network analysis and identified metabolic co-factors that might be beneficial as supplements to decrease fat in human liver. Here, we first assessed the tolerability of the combined metabolic cofactors including L-serine, N acetyl-L-cysteine (NAC), nicotinamide riboside (NR) and L-carnitine by performing a 7-day rat toxicology study. Second, we performed a 5-day human calibration study by supplementing metabolic cofactors and measured the kinetics of these metabolites in the plasma of nine subjects. We measured clinical parameters and observed no immediate side effects. Next, we generated untargeted metabolomics data to reveal the changes associated with the supplementation of these metabolic cofactors using genome-scale metabolic modelling and observed that such supplementation is significantly associated with lipid, amino acid and anti-oxidant metabolism. Finally, we generated an ordinary differential equation model to predict blood concentrations during daily long-term supplementation of these compounds and liver concentrations using pharmacokinetic modeling to adjust the doses of individual metabolic cofactors in human clinical studies.