Personal model-assisted identification of NAD+ and glutathione metabolism as intervention target in NAFLD

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 & 2 others Marja Riitta Taskinen, Jan Boren

Research output: Contribution to journalArticle

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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.

Original languageEnglish
Article number916
JournalMolecular Systems Biology
Volume13
Issue number3
DOIs
Publication statusPublished - 1 Mar 2017

Fingerprint

fatty liver
Metabolism
Liver
NAD
Identification (control systems)
Target
metabolism
Precursor
Glycine
Serine
Amino acids
Metabolomics
Lipoproteins
glycine (amino acid)
Glutathione
Model
serine
Biosynthesis
Nutrition
Metabolites

Cite this

Mardinoglu, A., Bjornson, E., Zhang, C., Klevstig, M., Söderlund, S., Ståhlman, M., ... Boren, J. (2017). Personal model-assisted identification of NAD+ and glutathione metabolism as intervention target in NAFLD. Molecular Systems Biology, 13(3), [916]. https://doi.org/10.15252/msb.20167422
Mardinoglu, Adil ; Bjornson, Elias ; Zhang, Cheng ; Klevstig, Martina ; Söderlund, Sanni ; Ståhlman, Marcus ; Adiels, Martin ; Hakkarainen, Antti ; Lundbom, Nina ; Kilicarslan, Murat ; Hallström, Björn M. ; Lundbom, Jesper ; Vergès, Bruno ; Barrett, Peter Hugh R ; Watts, Gerald F. ; Serlie, Mireille J. ; Nielsen, Jens ; Uhlén, Mathias ; Smith, Ulf ; Marschall, Hanns Ulrich ; Taskinen, Marja Riitta ; Boren, Jan. / Personal model-assisted identification of NAD+ and glutathione metabolism as intervention target in NAFLD. In: Molecular Systems Biology. 2017 ; Vol. 13, No. 3.
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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.",
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Mardinoglu, A, Bjornson, E, Zhang, C, Klevstig, M, Söderlund, S, Ståhlman, M, Adiels, M, Hakkarainen, A, Lundbom, N, Kilicarslan, M, Hallström, BM, Lundbom, J, Vergès, B, Barrett, PHR, Watts, GF, Serlie, MJ, Nielsen, J, Uhlén, M, Smith, U, Marschall, HU, Taskinen, MR & Boren, J 2017, 'Personal model-assisted identification of NAD+ and glutathione metabolism as intervention target in NAFLD' Molecular Systems Biology, vol. 13, no. 3, 916. https://doi.org/10.15252/msb.20167422

Personal model-assisted identification of NAD+ and glutathione metabolism as intervention target in NAFLD. / Mardinoglu, Adil; Bjornson, Elias; Zhang, Cheng; Klevstig, Martina; Söderlund, Sanni; Ståhlman, Marcus; Adiels, Martin; Hakkarainen, Antti; Lundbom, Nina; Kilicarslan, Murat; Hallström, Björn M.; Lundbom, Jesper; Vergès, Bruno; Barrett, Peter Hugh R; Watts, Gerald F.; Serlie, Mireille J.; Nielsen, Jens; Uhlén, Mathias; Smith, Ulf; Marschall, Hanns Ulrich; Taskinen, Marja Riitta; Boren, Jan.

In: Molecular Systems Biology, Vol. 13, No. 3, 916, 01.03.2017.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Personal model-assisted identification of NAD+ and glutathione metabolism as intervention target in NAFLD

AU - Mardinoglu, Adil

AU - Bjornson, Elias

AU - Zhang, Cheng

AU - Klevstig, Martina

AU - Söderlund, Sanni

AU - Ståhlman, Marcus

AU - Adiels, Martin

AU - Hakkarainen, Antti

AU - Lundbom, Nina

AU - Kilicarslan, Murat

AU - Hallström, Björn M.

AU - Lundbom, Jesper

AU - Vergès, Bruno

AU - Barrett, Peter Hugh R

AU - Watts, Gerald F.

AU - Serlie, Mireille J.

AU - Nielsen, Jens

AU - Uhlén, Mathias

AU - Smith, Ulf

AU - Marschall, Hanns Ulrich

AU - Taskinen, Marja Riitta

AU - Boren, Jan

PY - 2017/3/1

Y1 - 2017/3/1

N2 - 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.

AB - 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.

KW - glutathione

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KW - personalized genome-scale metabolic modeling

KW - serine

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DO - 10.15252/msb.20167422

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