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Previous studies have linked elevated acylcarnitine levels in the blood of patients with acute decompensation of cirrhosis to mitochondrial dysfunction, but their active role in damaging immune cells have remained unclear. Within the framework of the Grifols Chair Program, a collaborative research initiative to promote translational research in chronic liver disease between EF CLIF and Hospital Clínic de Barcelona-Institut d’Investigacions Biomèdiques August Pi i Sunyer (Barcelona, Spain), researchers of the European Network for Translational Research-Chronic Liver Failure (ENTR-CLIF), found that plasma levels of palmitoylcarnitine were significantly elevated in patients with acute decompensation of cirrhosis compared to healthy individuals.
“In addition to being elevated in the circulation of these patients, long-chain palmitoylcarnitine can induce cytokine secretion and cause mitochondrial dysfunction in leukocytes from healthy donors. Notably, our study demonstrates that inhibiting palmitoylcarnitine metabolism can counteract these harmful effects”, says first author in the paper Ingrid Zhang, postdoctoral researcher and clinician scientist currently at Charité–Universitaetsmedizin Berlin (Berlin, Germany).
Palmitoylcarnitine impaired mitochondrial function in circulating immune cells, leading to reduced expression of antioxidant genes and increased oxidative stress and. By suppressing the expression of heme oxygenase 1, an enzyme that confers protection in inflammatory conditions, palmitoylcarnitine triggered the release of proinflammatory cytokines, such as interleukin-8. Notably, these harmful effects were counteracted by blocking palmitoylcarnitine entry into the mitochondria and inhibiting its metabolism. The study also demonstrated that the presence of albumin, which has a high affinity for fatty acids and acylcarnitines, reduced the oxidative stress caused by palmitoylcarnitine in patients with acute decompensation of cirrhosis who received therapeutic albumin infusions.
The study adds to growing evidence of mitochondrial dysfunction as a critical factor in the progression of liver disease and its complications. By exploring how acylcarnitines contribute to immune cell impairment, these findings highlight immunometabolism as a promising avenue for future development of treatments and therapeutic interventions.
“The identification of palmitoylcarnitine as a driver of inflammation provides a critical avenue for therapeutic exploration in cirrhosis and ACLF. By integrating mitochondrial-targeted strategies and albumin, an already established therapy in the management of patients with acute decompensation of cirrhosis, clinicians and researchers can work towards restoring immune and metabolic homeostasis, ultimately improving outcomes for these high-risk patients”, said senior author in the paper Joan Clària, Director of the Grifols Chair and group leader of the Inflammation and Liver Disease group at IDIBAPS (Barcelona, Spain).
Other authors in the study are María Belén Sánchez-Rodríguez, Cristina López-Vicario, Mireia Casulleras, Marta Duran-Güell, Roger Flores-Costa, Ferran Aguilar, Michael Rothe, Paula Segalés, Carmen García-Ruiz, José C Fernández-Checa, Jonel Trebicka, and Vicente Arroyo.
Zhang IW, Sánchez-Rodríguez MB, López-Vicario C, Casulleras M, Duran-Güell M, Flores-Costa R, Aguilar F, Rothe M, Segalés P, García-Ruiz C, Fernández-Checa JC, Trebicka J, Arroyo V, Clària J. Palmitoylcarnitine impairs immunity in decompensated cirrhosis. JHEP Rep 2024; 6(11): 101187. DOI: 10.1016/j.jhepr.2024.101187
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