1. Mitochondrial dysfunction as a mechanistic biomarker in patients with non-alcoholic fatty liver disease (NAFLD).
- Author
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Ajaz S, McPhail MJ, Gnudi L, Trovato FM, Mujib S, Napoli S, Carey I, and Agarwal K
- Subjects
- Adult, Aged, Biomarkers blood, Case-Control Studies, Cross-Sectional Studies, Cytokines blood, Female, Humans, Male, Metabolomics methods, Middle Aged, Non-alcoholic Fatty Liver Disease blood, Up-Regulation, Urea blood, Young Adult, Carbamoyl-Phosphate Synthase (Ammonia) blood, Fibroblast Growth Factors blood, Mitochondria, Liver metabolism, Non-alcoholic Fatty Liver Disease metabolism, Ornithine Carbamoyltransferase blood
- Abstract
Background: Dysfunctional metabolism lies at the centre of the pathogenesis for Non-Alcoholic Fatty Liver Disease (NAFLD) and involves mitochondrial dysfunction, lipid dysmetabolism and oxidative stress. This study, for the first time, explores real-time energy changes in peripheral blood and corresponding metabolite changes, to investigate whether mitochondria-related immunometabolic biomarkers can predict progression in NAFLD., Methods: Thirty subjects divided into 3 groups were assessed: NAFLD with biopsy-proven mild fibrosis (n = 10), severe fibrosis (n = 10) and healthy controls (HC, n = 10). Mitochondrial functional analysis was performed in a Seahorse XFp analyzer in live peripheral blood mononuclear cells (PBMCs). Global metabolomics quantified a broad range of human plasma metabolites. Mitochondrial carbamoyl phosphate synthase 1(CPS-1), Ornithine transcarbamoylase (OTC), Fibroblast growth factor-21 (FGF-21) and a range of cytokines in plasma were measured by ELISA., Results: NAFLD patients with severe fibrosis demonstrated reduced maximal respiration (106 ± 25 versus 242 ± 62, p < 0.05) and reserve capacity (56 ± 16 versus 184 ± 42, p = 0.006) compared to mild/moderate fibrosis. Comparing mild/moderate vs severe liver fibrosis in patients with NAFLD, 14 out of 493 quantified metabolites were significantly changed (p < 0.05). Most of the amino acids modulated were the urea cycle (UC) components which included citrulline/ornithine ratio, arginine and glutamate. Plasma levels of CPS-1 and FGF-21 were significantly higher mild versus severe fibrosis in NAFLD patients. This novel panel generated an area under the ROC of 0.95, sensitivity of 100% and specificity 80% and p = 0.0007 (F1-F2 versus F3-F4)., Conclusion: Progression in NAFLD is associated with mitochondrial dysfunction and changes in metabolites associated with the urea cycle. We demonstrate a unique panel of mitochondrial-based, signatures which differentiate between stages of NAFLD., Lay Summary: Mitochondrial dysfunction in peripheral cells along with alterations in metabolites of urea cycle act as a sensor of hepatocyte mitochondrial damage. These changes can be measured in blood and together represent a unique panel of biomarkers for progression of fibrosis in NAFLD., (Copyright © 2020 Elsevier B.V. and Mitochondria Research Society. All rights reserved.)
- Published
- 2021
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