Abstract
The prevalence of non‐alcoholic fatty liver disease (NAFLD) continues to increase dramatically, and there is no approved medication for its treatment. Recently, we predicted the underlying molecular mechanisms involved in the progression of NAFLD using network analysis and identified metabolic cofactors that might be beneficial as supplements to decrease human liver fat. 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 human calibration study by supplementing combined metabolic cofactors and a control study to study the kinetics of these metabolites in the plasma of healthy subjects with and without supplementation. We measured clinical parameters and observed no immediate side effects. Next, we generated plasma metabolomics and inflammatory protein markers data to reveal the acute changes associated with the supplementation of the metabolic cofactors. We also integrated metabolomics data using personalized genome‐scale metabolic modeling and observed that such supplementation significantly affects the global human lipid, amino acid, and antioxidant metabolism. Finally, we predicted blood concentrations of these compounds during daily long‐term supplementation by generating an ordinary differential equation model and liver concentrations of serine by generating a pharmacokinetic model and finally adjusted the doses of individual metabolic cofactors for future human clinical trials.
Highlights
Hepatic steatosis (HS) is defined as the accumulation of large vacuoles of triglycerides in the liver (> 5.5% tissue weight) due to an imbalance between lipid deposition and lipid removal from the liver (Solinas et al, 2015; Francque et al, 2016; Samuel & Shulman, 2018)
Our model indicated that supplementation of L-carnitine as well as precursors of GSH and NAD+ including L-serine, N-acetyl-L-cysteine (NAC), and nicotinamide riboside (NR) would decrease liver fat accumulation by promoting the fat uptake and its oxidation in the mitochondria as well as generation of GSH required in the liver (Mardinoglu et al, 2017)
We performed a calibration study by supplementing metabolic cofactors including L-serine, NAC, NR, and L-carnitine based on our previous study, where we proposed that the supplementation of such cofactors may boost uptake and oxidation of fatty acids in mitochondria and eventually decreased the amount of fat in liver (Mardinoglu et al, 2017)
Summary
Hepatic steatosis (HS) is defined as the accumulation of large vacuoles of triglycerides in the liver (> 5.5% tissue weight) due to an imbalance between lipid deposition and lipid removal from the liver (Solinas et al, 2015; Francque et al, 2016; Samuel & Shulman, 2018). We generated a functional liver-specific genome-scale metabolic model (GEM) (Mardinoglu et al, 2014) and an integrated network (IN) (Lee et al, 2016) by merging GEMs with regulatory and protein–protein interaction networks. This integrative approach allows to reveal the key pathways, metabolites, and genes involved in the progression of liver diseases, and to make solid predictions that can be experimentally tested due to the known regulatory effect of other proteins on metabolism
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