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The acute effect of metabolic cofactor supplementation: a potential therapeutic strategy against non-alc33oholic fatty liver disease

Journal article
Authors C. Zhang
Elias Björnson
M. Arif
A. Tebani
A. Lovric
R. Benfeitas
M. Ozcan
K. Juszczak
W. Kim
J. T. Kim
G. Bidkhori
Marcus Ståhlman
P. O. Bergh
Martin Adiels
H. Turkez
M. R. Taskinen
J. Bosley
H. U. Marschall
J. Nielsen
M. Uhlen
Jan Borén
A. Mardinoglu
Published in Molecular Systems Biology
Volume 16
Issue 4
ISSN 1744-4292
Publication year 2020
Published at Institute of Medicine, Department of Molecular and Clinical Medicine
Language en
Keywords l-serine, N-acetyl-l-cysteine (NAC), nicotinamide riboside (NR), and, l-carnitine, NAFLD, systems medicine, growth-factor 21, serine, fibrosis, obesity, Biochemistry & Molecular Biology
Subject categories Biochemistry and Molecular Biology

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.

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