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

Artikel i vetenskaplig tidskrift
Författare Cheng Zhang
Elias Bjornson
Muhammad Arif
Abdellah Tebani
Alen Lovric
Rui Benfeitas
Mehmet Ozcan
Kajetan Juszczak
Woonghee Kim
Jung Tae Kim
Gholamreza Bidkhori
Marcus Ståhlman
Per-Olof Bergh
Martin Adiels
Hasan Turkez
Marja-Riitta Taskinen
Jim Bosley
Hanns-Ulrich Marschall
Jens Nielsen
Mathias Uhlén
Jan Borén
Adil Mardinoglu
Publicerad i Molecular systems biology
Volym 16
Nummer/häfte 4
Sidor e9495
ISSN 1744-4292
Publiceringsår 2020
Publicerad vid Wallenberglaboratoriet
Institutionen för medicin, avdelningen för molekylär och klinisk medicin
Sidor e9495
Språk en
Länkar dx.doi.org/10.15252/msb.209495
www.ncbi.nlm.nih.gov/entrez/query.f...
Ämnesord NAFLD, l-serine, N-acetyl-l-cysteine (NAC), nicotinamide riboside (NR), and l-carnitine, systems medicine
Ämneskategorier Endokrinologi och diabetes, Gastroenterologi

Sammanfattning

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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