Personal model‐assisted identification of NAD+ and glutathione metabolism as intervention target in NAFLD
Abstract To elucidate the molecular mechanisms underlying non‐alcoholic fatty liver disease (NAFLD), we recruited 86 subjects with varying degrees of hepatic steatosis (HS). We obtained experimental data on lipoprotein fluxes and used these individual measurements as personalized constraints of a he...
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Springer Nature
2017-03-01
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| Series: | Molecular Systems Biology |
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| Online Access: | https://doi.org/10.15252/msb.20167422 |
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| author | Adil Mardinoglu Elias Bjornson Cheng Zhang Martina Klevstig Sanni Söderlund Marcus Ståhlman Martin Adiels Antti Hakkarainen Nina Lundbom Murat Kilicarslan Björn M Hallström Jesper Lundbom Bruno Vergès Peter Hugh R Barrett Gerald F Watts Mireille J Serlie Jens Nielsen Mathias Uhlén Ulf Smith Hanns‐Ulrich Marschall Marja‐Riitta Taskinen Jan Boren |
| author_facet | Adil Mardinoglu Elias Bjornson Cheng Zhang Martina Klevstig Sanni Söderlund Marcus Ståhlman Martin Adiels Antti Hakkarainen Nina Lundbom Murat Kilicarslan Björn M Hallström Jesper Lundbom Bruno Vergès Peter Hugh R Barrett Gerald F Watts Mireille J Serlie Jens Nielsen Mathias Uhlén Ulf Smith Hanns‐Ulrich Marschall Marja‐Riitta Taskinen Jan Boren |
| author_sort | Adil Mardinoglu |
| collection | DOAJ |
| description | Abstract To elucidate the molecular mechanisms underlying non‐alcoholic fatty liver disease (NAFLD), we recruited 86 subjects with varying degrees of hepatic steatosis (HS). We obtained experimental data on lipoprotein fluxes and used these individual measurements as personalized constraints of a hepatocyte genome‐scale metabolic model to investigate metabolic differences in liver, taking into account its interactions with other tissues. Our systems level analysis predicted an altered demand for NAD+ and glutathione (GSH) in subjects with high HS. Our analysis and metabolomic measurements showed that plasma levels of glycine, serine, and associated metabolites are negatively correlated with HS, suggesting that these GSH metabolism precursors might be limiting. Quantification of the hepatic expression levels of the associated enzymes further pointed to altered de novo GSH synthesis. To assess the effect of GSH and NAD+ repletion on the development of NAFLD, we added precursors for GSH and NAD+ biosynthesis to the Western diet and demonstrated that supplementation prevents HS in mice. In a proof‐of‐concept human study, we found improved liver function and decreased HS after supplementation with serine (a precursor to glycine) and hereby propose a strategy for NAFLD treatment. |
| format | Article |
| id | doaj-art-e43610ba34b24032ab9bcfbc35617cd8 |
| institution | Kabale University |
| issn | 1744-4292 |
| language | English |
| publishDate | 2017-03-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | Molecular Systems Biology |
| spelling | doaj-art-e43610ba34b24032ab9bcfbc35617cd82025-01-12T12:45:33ZengSpringer NatureMolecular Systems Biology1744-42922017-03-0113311710.15252/msb.20167422Personal model‐assisted identification of NAD+ and glutathione metabolism as intervention target in NAFLDAdil Mardinoglu0Elias Bjornson1Cheng Zhang2Martina Klevstig3Sanni Söderlund4Marcus Ståhlman5Martin Adiels6Antti Hakkarainen7Nina Lundbom8Murat Kilicarslan9Björn M Hallström10Jesper Lundbom11Bruno Vergès12Peter Hugh R Barrett13Gerald F Watts14Mireille J Serlie15Jens Nielsen16Mathias Uhlén17Ulf Smith18Hanns‐Ulrich Marschall19Marja‐Riitta Taskinen20Jan Boren21Science for Life Laboratory, KTH – Royal Institute of TechnologyDepartment of Biology and Biological Engineering, Chalmers University of TechnologyScience for Life Laboratory, KTH – Royal Institute of TechnologyDepartment of Molecular and Clinical Medicine, University of Gothenburg, and Sahlgrenska University HospitalResearch programs Unit, Diabetes and Obesity, Helsinki University Hospital, University of HelsinkiDepartment of Molecular and Clinical Medicine, University of Gothenburg, and Sahlgrenska University HospitalDepartment of Molecular and Clinical Medicine, University of Gothenburg, and Sahlgrenska University HospitalDepartment of Radiology, HUS Medical Imaging Center, Helsinki University Central Hospital, University of HelsinkiDepartment of Radiology, HUS Medical Imaging Center, Helsinki University Central Hospital, University of HelsinkiDepartment of Endocrinology and Metabolism, Academic Medical Center, University of AmsterdamScience for Life Laboratory, KTH – Royal Institute of TechnologyDepartment of Radiology, HUS Medical Imaging Center, Helsinki University Central Hospital, University of HelsinkiDepartment of Endocrinology–Diabetology, University Hospital and INSERM CRI 866Faculty of Engineering, Computing and Mathematics, University of Western AustraliaMetabolic Research Centre, Cardiovascular Medicine, Royal Perth Hospital, School of Medicine and Pharmacology, University of Western AustraliaDepartment of Endocrinology and Metabolism, Academic Medical Center, University of AmsterdamScience for Life Laboratory, KTH – Royal Institute of TechnologyScience for Life Laboratory, KTH – Royal Institute of TechnologyDepartment of Molecular and Clinical Medicine, University of Gothenburg, and Sahlgrenska University HospitalDepartment of Molecular and Clinical Medicine, University of Gothenburg, and Sahlgrenska University HospitalResearch programs Unit, Diabetes and Obesity, Helsinki University Hospital, University of HelsinkiDepartment of Molecular and Clinical Medicine, University of Gothenburg, and Sahlgrenska University HospitalAbstract To elucidate the molecular mechanisms underlying non‐alcoholic fatty liver disease (NAFLD), we recruited 86 subjects with varying degrees of hepatic steatosis (HS). We obtained experimental data on lipoprotein fluxes and used these individual measurements as personalized constraints of a hepatocyte genome‐scale metabolic model to investigate metabolic differences in liver, taking into account its interactions with other tissues. Our systems level analysis predicted an altered demand for NAD+ and glutathione (GSH) in subjects with high HS. Our analysis and metabolomic measurements showed that plasma levels of glycine, serine, and associated metabolites are negatively correlated with HS, suggesting that these GSH metabolism precursors might be limiting. Quantification of the hepatic expression levels of the associated enzymes further pointed to altered de novo GSH synthesis. To assess the effect of GSH and NAD+ repletion on the development of NAFLD, we added precursors for GSH and NAD+ biosynthesis to the Western diet and demonstrated that supplementation prevents HS in mice. In a proof‐of‐concept human study, we found improved liver function and decreased HS after supplementation with serine (a precursor to glycine) and hereby propose a strategy for NAFLD treatment.https://doi.org/10.15252/msb.20167422glutathioneNAFLDpersonalized genome‐scale metabolic modelingserine |
| spellingShingle | Adil Mardinoglu Elias Bjornson Cheng Zhang Martina Klevstig Sanni Söderlund Marcus Ståhlman Martin Adiels Antti Hakkarainen Nina Lundbom Murat Kilicarslan Björn M Hallström Jesper Lundbom Bruno Vergès Peter Hugh R Barrett Gerald F Watts Mireille J Serlie Jens Nielsen Mathias Uhlén Ulf Smith Hanns‐Ulrich Marschall Marja‐Riitta Taskinen Jan Boren Personal model‐assisted identification of NAD+ and glutathione metabolism as intervention target in NAFLD Molecular Systems Biology glutathione NAFLD personalized genome‐scale metabolic modeling serine |
| title | Personal model‐assisted identification of NAD+ and glutathione metabolism as intervention target in NAFLD |
| title_full | Personal model‐assisted identification of NAD+ and glutathione metabolism as intervention target in NAFLD |
| title_fullStr | Personal model‐assisted identification of NAD+ and glutathione metabolism as intervention target in NAFLD |
| title_full_unstemmed | Personal model‐assisted identification of NAD+ and glutathione metabolism as intervention target in NAFLD |
| title_short | Personal model‐assisted identification of NAD+ and glutathione metabolism as intervention target in NAFLD |
| title_sort | personal model assisted identification of nad and glutathione metabolism as intervention target in nafld |
| topic | glutathione NAFLD personalized genome‐scale metabolic modeling serine |
| url | https://doi.org/10.15252/msb.20167422 |
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