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Assessing the role of amino acids in systemic inflammation and organ failure in patients with ACLF

Zaccherini, G; Aguilar, F; Caraceni, P; Clària, J; Lozano, JJ; Fenaille, F; Castelli, F; ... Arroyo, V; + view all (2021) Assessing the role of amino acids in systemic inflammation and organ failure in patients with ACLF. Journal of Hepatology , 74 (5) pp. 1117-1131. 10.1016/j.jhep.2020.11.035. Green open access

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Abstract

Background and aims: Intense systemic inflammatory responses and the existence of organ failures are the hallmarks of acute-on-chronic liver failure (ACLF) that complicates cirrhosis. Little is known about the role of amino acids in systemic inflammation and organ failures in this syndrome. / Methods: The blood metabolomic data base of the CANONIC study (comprising 137 metabolites with 43% related to amino acids) obtained in 181 patients with ACLF and 650 with acute decompensation without ACLF [AD]) was reanalyzed for amino acids, in particular identifying 9 modules of co-regulated metabolites. We also compared blood metabolite levels between ACLF and AD. / Results: The main findings in ACLF were: (1) Metabolite modules were increased in parallel with increased levels of markers of systemic inflammation and oxidative stress. (2) Seventy percent of proteinogenic amino acids were present and most were increased. (3) A metabolic network, comprising the amino acids aspartate, glutamate, the serine-glycine one-carbon metabolism (folate cycle), and methionine cycle, was activated, suggesting increased purine and pyrimidine nucleotide synthesis. (4) Cystathionine, L-cystine, glutamate, pyroglutamate, involved in the transsulfuration pathway (a methionine cycle branch) were increased, consistent with an increased synthesis of antioxidant glutathione. (5) Intermediates of the catabolism of 5 out of the 6 ketogenic amino acids were increased. (6) Spermidine (a polyamine inducer of autophagy with anti-inflammatory effects) had decreased levels. / Conclusions: In ACLF, blood amino acids fueled protein and nucleotide synthesis required by intense systemic inflammatory responses. Ketogenic amino acids were extensively catabolized to produce energy substrates in peripheral organs, an effect that was insufficient because organs failed. Finally, the decrease in spermidine levels may cause a defect in autophagy contributing to proinflammatory phenotype in ACLF.

Type: Article
Title: Assessing the role of amino acids in systemic inflammation and organ failure in patients with ACLF
Location: Netherlands
Open access status: An open access version is available from UCL Discovery
DOI: 10.1016/j.jhep.2020.11.035
Publisher version: https://doi.org/10.1016/j.jhep.2020.11.035
Language: English
Additional information: This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions.
Keywords: Multiorgan failure; Small-molecules; Biomass; Immunity; Anabolic metabolism; Dormancy
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine > Inst for Liver and Digestive Hlth
URI: https://discovery.ucl.ac.uk/id/eprint/10119300
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