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.

and l-carnitine

nicotinamide riboside (NR)

NAFLD

N-acetyl-l-cysteine (NAC)

systems medicine

l-serine

Author

C. Zhang

Zhengzhou University

Royal Institute of Technology (KTH)

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

Royal Institute of Technology (KTH)

Karolinska University Hospital

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 Boren

University of Gothenburg

Adil Mardinoglu

King's College London

Royal Institute of Technology (KTH)

Molecular Systems Biology

1744-4292 (ISSN)

Vol. 16 4 e9495

Subject Categories

Pharmaceutical Sciences

Other Clinical Medicine

Pharmacology and Toxicology

DOI

10.15252/msb.209495

PubMed

32337855

More information

Latest update

2/15/2021