Palmitoylcarnitine impairs immunity in decompensated cirrhosis

• DOI: 10.1016/j.jhepr.2024.101187
• Publication Date: 2024-08-23T10:38:07Z
• Authors: Ingrid Wei Zhang; María Belén Sánch...; Cristina López-Vi...; Mireia Casulleras; Marta Duran-Güell; Roger Flores-Costa; Ferran Aguilar; Michael Rothe; Paula Segalés; Carmen García-Ruiz; José C. Fernández...; Jonel Trebicka; Vicente Arroyo; Joan Clària
• Keywords: Palmitoylcarnitine

Highlights•Palmitoylcarnitine is elevated in plasma of patients with acute decompensation cirrhosis.•This long-chain acylcarnitine induces mitochondrial oxidative stress leukocytes.•It suppresses heme oxygenase 1 and the secretion proinflammatory cytokines.•These effects were prevented by blocking entry palmitoylcarnitine its oxidation mitochondria.AbstractBackground & AimsIn cirrhosis, (AD) correlates a hyperinflammatory state driven dysfunction, which significant factor progression to acute-on-chronic liver failure (ACLF). Elevated circulating levels acylcarnitines, indicative are predictors mortality ACLF patients. Our hypothesis posits that acylcarnitines not only act as biomarkers but actively exert detrimental on immune cells.MethodsPlasma measured 20 AD cirrhosis 10 healthy subjects. The selected medium- function investigated peripheral leukocytes from donors determining membrane potential (ΔΨm) respiration using JC-1 dye Agilent Seahorse XF technology. Changes regarding ultrastructure redox system assessed transmission electron microscopy, gene protein expression analysis.ResultsPlasma several species significantly compared subjects, alongside increased inflammatory mediators (cytokines chemokines). Notably, (C16:0-carnitine, 1.51-fold higher, p=0.0059) impaired ΔΨm reduced spare respiratory capacity mononuclear leukocytes. Additionally, C16:0-carnitine induced stress, suppressed antioxidant HMOX1, CXCL8 IL-8 release. Etomoxir, blocks into mitochondria, reversed suppression HMOX1. Similarly, trimetazidine, fatty acid beta-oxidation inhibitor, C16:0-carnitine-induced expression. Importantly, impairment caused less severe presence albumin, standard therapy for cirrhosis.ConclusionsOur findings suggest contribute dysfunction cells, thereby contributing development associated cirrhosis.Impact implicationsPatients live (ACLF) display systemic leukocyte dysfunction. We discovered apart being circulation these patients, able elicit cytokine paired donors. In particular, we could show inhibiting metabolism reverse effects. underline importance immunometabolism treatment target ACLF.Graphical abstract