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

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Zhang , C , Bjornson , E , Arif , M , Tebani , A , Lovric , A , Benfeitas , R , Ozcan , M , Juszczak , K , Kim , W , Kim , J T , Bidkhori , G , Ståhlman , M , Bergh , P-O , Adiels , M , Turkez , H , Taskinen , M-R , Bosley , J , Marschall , H-U , Nielsen , J , Uhlén , M , Borén , J & Mardinoglu , A 2020 , ' The acute effect of metabolic cofactor supplementation : a potential therapeutic strategy against non-alcoholic fatty liver disease ' , Molecular Systems Biology , vol. 16 , no. 4 , e9495 . https://doi.org/10.15252/msb.209495

Title: The acute effect of metabolic cofactor supplementation : a potential therapeutic strategy against non-alcoholic fatty liver disease
Author: Zhang, Cheng; Bjornson, Elias; Arif, Muhammad; Tebani, Abdellah; Lovric, Alen; Benfeitas, Rui; Ozcan, Mehmet; Juszczak, Kajetan; Kim, Woonghee; Kim, Jung Tae; Bidkhori, Gholamreza; Ståhlman, Marcus; Bergh, Per-Olof; Adiels, Martin; Turkez, Hasan; Taskinen, Marja-Riitta; Bosley, Jim; Marschall, Hanns-Ulrich; Nielsen, Jens; Uhlén, Mathias; Borén, Jan; Mardinoglu, Adil
Contributor: University of Helsinki, HUS Heart and Lung Center
Date: 2020-04-27
Language: eng
Number of pages: 16
Belongs to series: Molecular Systems Biology
ISSN: 1744-4292
URI: http://hdl.handle.net/10138/315744
Abstract: 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.
Subject: l-serine, N-acetyl-l-cysteine (NAC), nicotinamide riboside (NR), and l-carnitine
NAFLD
systems medicine
3121 General medicine, internal medicine and other clinical medicine
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