Zhang, Ingrid W.; Curto, Anna; Lopez-Vicario, Cristina; Casulleras, Mireia; Duran-Guell, Marta; Flores-Costa, Roger; Colsch, Benoit; Aguilar, Ferran; Aransay, Ana M.; Lozano, Juan Jose; Hernandez-Tejero, Maria; Toapanta, David; Fernandez, Javier; Arroyo, Vicente; Claria, Joan published the artcile< Mitochondrial dysfunction governs immunometabolism in leukocytes of patients with acute-on-chronic liver failure>, Category: esters-buliding-blocks, the main research area is gene expression mitochondrial dysfunction immunometabolism leukocyte acute liver failure; ACLF; RNA-seq; acute decompensated cirrhosis; immune cells; metabolic phenotype; mitochondria.
Patients with acute-on-chronic liver failure (ACLF) present a systemic hyperinflammatory response associated with increased circulating levels of small-mol. metabolites. To investigate whether these alterations reflect inadequate cell energy output, we assessed mitochondrial morphol. and central metabolic pathways with emphasis on the tricarboxylic acid (TCA) cycle in peripheral leukocytes from patients with acutely decompensated (AD) cirrhosis, with and without ACLF.The study included samples from patients with AD cirrhosis (108 without and 128 with ACLF) and 41 healthy individuals. Leukocyte mitochondrial ultrastructure was visualized by transmission electron microscopy and cytosolic and mitochondrial metabolic fluxes were determined by assessing NADH/FADH2 production from various substrates. Plasma GDF15 and FGF21 were determined by Luminex and acylcarnitines by LC-MS/MS. Gene expression was analyzed by RNA-sequencing and PCR-based glucose metabolism profiler array.Mitochondrial ultrastructure in patients with advanced cirrhosis was distinguished by cristae rarefication and swelling. The number of mitochondria per leukocyte was higher in patients, accompanied by a reduction in their size. Increased FGF21 and C6:0- and C8:0-carnitine predicted mortality whereas GDF15 strongly correlated with a gene set signature related to leukocyte activation. Metabolic flux analyses revealed increased energy production in mononuclear leukocytes from patients with preferential involvement of extra-mitochondrial pathways, supported by upregulated expression of genes encoding enzymes of the glycolytic and pentose phosphate pathways. In patients with ACLF, mitochondrial function anal. uncovered break-points in the TCA cycle at the isocitrate dehydrogenase and succinate dehydrogenase level, which were bridged by anaplerotic reactions involving glutaminolysis and nucleoside metabolismOur findings provide evidence at the cellular, organelle and biochem. levels that severe mitochondrial dysfunction governs immunometabolism in leukocytes from patients with AD cirrhosis and ACLF.Patients at advanced stages of liver disease have dismal prognosis due to vital organ failures and the lack of treatment options. In this study, we report that the functioning of mitochondria, which are known as the cell powerhouse, is severely impaired in leukocytes of these patients, probably as a consequence of intense inflammation. Mitochondrial dysfunction is therefore a hallmark of advanced liver disease.
Journal of Hepatology published new progress about Activating transcription factor 4 Role: BSU (Biological Study, Unclassified), BIOL (Biological Study). 112-63-0 belongs to class esters-buliding-blocks, and the molecular formula is C19H34O2, Category: esters-buliding-blocks.
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