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Arif, M., Klevstig, M., Benfeitas, R., Doran, S., Turkez, H., Uhlén, M., . . . Boren, J. (2021). Integrative transcriptomic analysis of tissue-specific metabolic crosstalk after myocardial infarction. eLIFE, 10, Article ID e66921.
Open this publication in new window or tab >>Integrative transcriptomic analysis of tissue-specific metabolic crosstalk after myocardial infarction
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2021 (English)In: eLIFE, E-ISSN 2050-084X, Vol. 10, article id e66921Article in journal (Refereed) Published
Abstract [en]

Myocardial infarction (MI) promotes a range of systemic effects, many of which are unknown. Here, we investigated the alterations associated with MI progression in heart and other metabolically active tissues (liver, skeletal muscle, and adipose) in a mouse model of MI (induced by ligating the left ascending coronary artery) and sham-operated mice. We performed a genomewide transcriptomic analysis on tissue samples obtained 6- and 24 hr post MI or sham operation. By generating tissue-specific biological networks, we observed: (1) dysregulation in multiple biological processes (including immune system, mitochondrial dysfunction, fatty-acid beta-oxidation, and RNA and protein processing) across multiple tissues post MI and (2) tissue-specific dysregulation in biological processes in liver and heart post MI. Finally, we validated our findings in two independent MI cohorts. Overall, our integrative analysis highlighted both common and specific biological responses to MI across a range of metabolically active tissues.

National Category
Biological Sciences
Identifiers
urn:nbn:se:su:diva-195172 (URN)10.7554/eLife.66921 (DOI)000661322200001 ()33972017 (PubMedID)
Available from: 2021-08-10 Created: 2021-08-10 Last updated: 2022-02-25Bibliographically approved
Zhang, C., Bjornson, E., Arif, M., Tebani, A., Lovric, A., Benfeitas, R., . . . Mardinoglu, A. (2020). The acute effect of metabolic cofactor supplementation: a potential therapeutic strategy against non-alc33oholic fatty liver disease. Molecular Systems Biology, 16(4), Article ID e9495.
Open this publication in new window or tab >>The acute effect of metabolic cofactor supplementation: a potential therapeutic strategy against non-alc33oholic fatty liver disease
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2020 (English)In: Molecular Systems Biology, ISSN 1744-4292, E-ISSN 1744-4292, Vol. 16, no 4, article id e9495Article in journal (Refereed) Published
Abstract [en]

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.

Keywords
l-serine, N-acetyl-l-cysteine (NAC), nicotinamide riboside (NR), and l-carnitine, NAFLD, systems medicine
National Category
Biological Sciences Pharmaceutical Sciences
Identifiers
urn:nbn:se:su:diva-181719 (URN)10.15252/msb.209495 (DOI)000530421100005 ()32337855 (PubMedID)2-s2.0-85084170451 (Scopus ID)
Available from: 2020-06-02 Created: 2020-06-02 Last updated: 2022-09-07Bibliographically approved
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Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0002-3721-8586

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