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

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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 & 2 more Jan Borén, Adil Mardinoglu

Original languageEnglish
Pages (from-to)e9495
JournalMolecular Systems Biology
Volume16
Issue number4
DOIs
Publication statusPublished - 1 Apr 2020

King's Authors

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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