Palmitoylcarnitine impairs immunity in decompensated cirrhosis
Ingrid W. Zhang, María Belén Sánchez-Rodríguez, Cristina López‐Vicario, Mireia Casulleras, Marta Duran‐Güell, Roger Flores‐Costa, Ferrán Aguilar, Michael Rothe, Paula Segalés, Carmen García‐Ruiz, José C. Fernández‐Checa, Jonel Trebicka, Vicente Arroyo, Joan Clària
Abstract
Background & Aims In patients with cirrhosis, acute decompensation (AD) correlates with a hyperinflammatory state driven by mitochondrial dysfunction, which is a significant factor in the progression to acute-on-chronic liver failure (ACLF). Elevated circulating levels of acylcarnitines, indicative of mitochondrial dysfunction, are predictors of mortality in ACLF patients. Our hypothesis posits that acylcarnitines not only act as biomarkers but actively exert detrimental effects on circulating immune cells. Methods Plasma acylcarnitine levels were measured in 20 patients with AD cirrhosis and 10 healthy subjects. The effects of selected medium- and long-chain acylcarnitines on mitochondrial function were investigated in peripheral leukocytes from healthy donors by determining mitochondrial membrane potential (ΔΨm) and mitochondrial respiration using the JC-1 dye and Agilent Seahorse XF technology. Changes regarding mitochondrial ultrastructure and redox system were assessed by transmission electron microscopy, and gene and protein expression analysis. Results Plasma levels of several acylcarnitine species were significantly elevated in AD patients compared to healthy subjects, alongside increased levels of inflammatory mediators (cytokines and chemokines). Notably, the long-chain acylcarnitine palmitoylcarnitine (C16:0-carnitine, 1.51-fold higher, p=0.0059) impaired ΔΨm and reduced the spare respiratory capacity of peripheral mononuclear leukocytes. Additionally, C16:0-carnitine induced mitochondrial oxidative stress, suppressed the antioxidant gene HMOX1 , and increased CXCL8 expression and IL-8 release. Etomoxir, which blocks acylcarnitine entry into mitochondria, reversed the suppression of HMOX1 . Similarly, trimetazidine, a fatty acid beta-oxidation inhibitor, prevented C16:0-carnitine-induced CXCL8 expression. Importantly, oxidative stress and ΔΨm impairment caused by C16:0-carnitine were less severe in the presence of albumin, a standard therapy for AD cirrhosis. Conclusions Our findings suggest that long-chain acylcarnitines contribute to mitochondrial dysfunction in immune cells, thereby contributing to the development of immune dysfunction associated with cirrhosis. Impact and implications Patients with acute decompensation of cirrhosis and acute-on-chronic live failure (ACLF) display a systemic hyperinflammatory state and leukocyte mitochondrial dysfunction. We discovered that apart from being increased in the circulation of these patients, the long-chain palmitoylcarnitine is able to elicit cytokine secretion paired with mitochondrial dysfunction in leukocytes from healthy donors. In particular, we could show that inhibiting the metabolism of palmitoylcarnitine could reverse these detrimental effects. Our findings underline the importance of immunometabolism as a treatment target in patients with acute decompensation of cirrhosis and ACLF.