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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\n                    <jats:sc>l<\/jats:sc>\n                    \u2010serine,\n                    <jats:italic>N<\/jats:italic>\n                    \u2010acetyl\u2010\n                    <jats:sc>l<\/jats:sc>\n                    \u2010cysteine (NAC), nicotinamide riboside (NR), and\n                    <jats:sc>l<\/jats:sc>\n                    \u2010carnitine by performing a 7\u2010day 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\u2010scale 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\u2010term supplementation by generating an ordinary differential equation\u00a0model and liver concentrations of serine by generating a pharmacokinetic model and finally adjusted the doses of individual metabolic cofactors for future human clinical trials.\n                  <\/jats:p>","DOI":"10.15252\/msb.209495","type":"journal-article","created":{"date-parts":[[2020,4,27]],"date-time":"2020-04-27T03:05:39Z","timestamp":1587956739000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":48,"title":["The acute effect of metabolic cofactor supplementation: a potential therapeutic strategy against non\u2010alcoholic fatty liver disease"],"prefix":"10.1038","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3721-8586","authenticated-orcid":false,"given":"Cheng","family":"Zhang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elias","family":"Bjornson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Muhammad","family":"Arif","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8901-2678","authenticated-orcid":false,"given":"Abdellah","family":"Tebani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alen","family":"Lovric","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7972-0083","authenticated-orcid":false,"given":"Rui","family":"Benfeitas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1222-2802","authenticated-orcid":false,"given":"Mehmet","family":"Ozcan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kajetan","family":"Juszczak","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Woonghee","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jung Tae","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gholamreza","family":"Bidkhori","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcus","family":"St\u00e5hlman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9993-6965","authenticated-orcid":false,"given":"Per\u2010Olof","family":"Bergh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin","family":"Adiels","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hasan","family":"Turkez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marja\u2010Riitta","family":"Taskinen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jim","family":"Bosley","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hanns\u2010Ulrich","family":"Marschall","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9955-6003","authenticated-orcid":false,"given":"Jens","family":"Nielsen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4858-8056","authenticated-orcid":false,"given":"Mathias","family":"Uhl\u00e9n","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0786-8091","authenticated-orcid":false,"given":"Jan","family":"Bor\u00e9n","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4254-6090","authenticated-orcid":false,"given":"Adil","family":"Mardinoglu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2020,4,27]]},"reference":[{"key":"BFMSB209495_CR1","doi-asserted-by":"crossref","first-page":"e0186459","DOI":"10.1371\/journal.pone.0186459","volume":"12","author":"SE Airhart","year":"2017","unstructured":"Airhart SE, Shireman LM, Risler LJ, Anderson GD, Gowda GAN, Raftery D, Tian R, Shen DD, O'Brien KD (2017) An open\u2010label, non\u2010randomized study of the pharmacokinetics of the nutritional supplement nicotinamide riboside (NR) and its effects on blood NAD plus levels in healthy volunteers. 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