The acute effect of metabolic cofactor supplementation: a potential therapeutic strategy against non-alcoholic fatty liver disease
Journal article, 2020
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.
systems medicine
and l-carnitine
l-serine
N-acetyl-l-cysteine (NAC)
NAFLD
nicotinamide riboside (NR)
Author
C. Zhang
Royal Institute of Technology (KTH)
Zhengzhou University
Elias Björnson
University of Gothenburg
Chalmers, Biology and Biological Engineering, Systems and Synthetic Biology
Muhammad Arif
Royal Institute of Technology (KTH)
Abdellah Tebani
Royal Institute of Technology (KTH)
Alen Lovric
Karolinska University Hospital
Royal Institute of Technology (KTH)
Rui Benfeitas
Royal Institute of Technology (KTH)
Stockholm University
Mehmet Ozcan
Royal Institute of Technology (KTH)
Kajetan Juszczak
Royal Institute of Technology (KTH)
Woonghee Kim
Royal Institute of Technology (KTH)
Jung Tae Kim
Royal Institute of Technology (KTH)
Gholamreza Bidkhori
King's College London
Marcus Stahlman
University of Gothenburg
Per-Olof Bergh
University of Gothenburg
Martin Adiels
University of Gothenburg
Hasan Turkez
Atatürk University
Marja-Riitta Taskinen
University of Helsinki
Jim Bosley
Clermont Bosley LLC
Hanns-Ulrich Marschall
University of Gothenburg
Jens B Nielsen
Chalmers, Biology and Biological Engineering, Systems and Synthetic Biology
Mathias Uhlen
Royal Institute of Technology (KTH)
Jan Borén
University of Gothenburg
Adil Mardinoglu
Royal Institute of Technology (KTH)
King's College London
Molecular Systems Biology
17444292 (eISSN)
Vol. 16 4 e9495Subject Categories (SSIF 2011)
Pharmaceutical Sciences
Other Clinical Medicine
Pharmacology and Toxicology
DOI
10.15252/msb.209495
PubMed
32337855