Ferroptosis is a targetable detrimental factor in metabolic dysfunction-associated steatotic liver disease.

Autor: Peleman C; Laboratory of Experimental Medicine and Pediatrics, Infla-Med Centre of Excellence, University of Antwerp, Antwerp, Belgium.; Department of Gastroenterology and Hepatology, Antwerp University Hospital, Antwerp, Belgium.; Cell Death Signaling Lab, Department of Biomedical Sciences, University of Antwerp, Antwerp, Belgium., Hellemans S; Laboratory of Experimental Medicine and Pediatrics, Infla-Med Centre of Excellence, University of Antwerp, Antwerp, Belgium., Veeckmans G; Cell Death Signaling Lab, Department of Biomedical Sciences, University of Antwerp, Antwerp, Belgium., Arras W; Laboratory of Experimental Medicine and Pediatrics, Infla-Med Centre of Excellence, University of Antwerp, Antwerp, Belgium., Zheng H; Department of Pathology and Biological Responses, Nagoya University Graduate School of Medicine, Nagoya, Japan., Koeken I; Cell Death Signaling Lab, Department of Biomedical Sciences, University of Antwerp, Antwerp, Belgium.; VIB-UGent Center for Inflammation Research, Ghent, Belgium., Van San E; Cell Death Signaling Lab, Department of Biomedical Sciences, University of Antwerp, Antwerp, Belgium., Hassannia B; Cell Death Signaling Lab, Department of Biomedical Sciences, University of Antwerp, Antwerp, Belgium.; VIB-UGent Center for Inflammation Research, Ghent, Belgium.; Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium., Walravens M; Cell Death Signaling Lab, Department of Biomedical Sciences, University of Antwerp, Antwerp, Belgium., Kayirangwa E; Laboratory of Experimental Medicine and Pediatrics, Infla-Med Centre of Excellence, University of Antwerp, Antwerp, Belgium., Beyene NT; Laboratory of Experimental Medicine and Pediatrics, Infla-Med Centre of Excellence, University of Antwerp, Antwerp, Belgium.; Department of Gastroenterology and Hepatology, Antwerp University Hospital, Antwerp, Belgium., Van Herck MA; Laboratory of Experimental Medicine and Pediatrics, Infla-Med Centre of Excellence, University of Antwerp, Antwerp, Belgium.; Department of Gastroenterology and Hepatology, Antwerp University Hospital, Antwerp, Belgium., De Vos WH; Laboratory of Cell Biology & Histology, Department of Veterinary Sciences, University of Antwerp, Antwerp, Belgium.; Antwerp Centre for Advanced Microscopy (ACAM), University of Antwerp, Antwerp, Belgium.; µNEURO Research Excellence Consortium on Multimodal Neuromics, University of Antwerp, Antwerp, Belgium., Pintelon I; Laboratory of Cell Biology & Histology, Department of Veterinary Sciences, University of Antwerp, Antwerp, Belgium.; Antwerp Centre for Advanced Microscopy (ACAM), University of Antwerp, Antwerp, Belgium.; µNEURO Research Excellence Consortium on Multimodal Neuromics, University of Antwerp, Antwerp, Belgium., van Nassauw L; Department of ASTARC, Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium., Oosterlinck B; Laboratory of Experimental Medicine and Pediatrics, Infla-Med Centre of Excellence, University of Antwerp, Antwerp, Belgium., Smet A; Laboratory of Experimental Medicine and Pediatrics, Infla-Med Centre of Excellence, University of Antwerp, Antwerp, Belgium., Vits L; Laboratory of Experimental Medicine and Pediatrics, Infla-Med Centre of Excellence, University of Antwerp, Antwerp, Belgium., Dirinck E; Laboratory of Experimental Medicine and Pediatrics, Infla-Med Centre of Excellence, University of Antwerp, Antwerp, Belgium.; Department of Endocrinology, Diabetology and Metabolism, Antwerp University Hospital, Edegem, Belgium., Verrijken A; Laboratory of Experimental Medicine and Pediatrics, Infla-Med Centre of Excellence, University of Antwerp, Antwerp, Belgium.; Department of Endocrinology, Diabetology and Metabolism, Antwerp University Hospital, Edegem, Belgium., De Man J; Laboratory of Experimental Medicine and Pediatrics, Infla-Med Centre of Excellence, University of Antwerp, Antwerp, Belgium., Van Eyck A; Laboratory of Experimental Medicine and Pediatrics, Infla-Med Centre of Excellence, University of Antwerp, Antwerp, Belgium.; Department of Pediatrics, Antwerp University Hospital, Edegem, Belgium., Kwanten WJ; Laboratory of Experimental Medicine and Pediatrics, Infla-Med Centre of Excellence, University of Antwerp, Antwerp, Belgium.; Department of Gastroenterology and Hepatology, Antwerp University Hospital, Antwerp, Belgium., Vonghia L; Laboratory of Experimental Medicine and Pediatrics, Infla-Med Centre of Excellence, University of Antwerp, Antwerp, Belgium.; Department of Gastroenterology and Hepatology, Antwerp University Hospital, Antwerp, Belgium., Driessen A; Department of Pathology, Antwerp University Hospital, Antwerp, Belgium.; Department of Molecular Imaging, Pathology, Radiotherapy, Oncology, Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium., Augustyns K; Laboratory of Medicinal Chemistry, University of Antwerp, Antwerp, Belgium., Toyokuni S; Department of Pathology and Biological Responses, Nagoya University Graduate School of Medicine, Nagoya, Japan.; Center for Low-temperature Plasma Sciences, Nagoya University, Nagoya, Japan., De Winter B; Laboratory of Experimental Medicine and Pediatrics, Infla-Med Centre of Excellence, University of Antwerp, Antwerp, Belgium.; Department of Gastroenterology and Hepatology, Antwerp University Hospital, Antwerp, Belgium., Van Steenkiste C; Laboratory of Experimental Medicine and Pediatrics, Infla-Med Centre of Excellence, University of Antwerp, Antwerp, Belgium.; Department of Gastroenterology and Hepatology, Antwerp University Hospital, Antwerp, Belgium., Francque S; Laboratory of Experimental Medicine and Pediatrics, Infla-Med Centre of Excellence, University of Antwerp, Antwerp, Belgium.; Department of Gastroenterology and Hepatology, Antwerp University Hospital, Antwerp, Belgium., Vanden Berghe T; Cell Death Signaling Lab, Department of Biomedical Sciences, University of Antwerp, Antwerp, Belgium. tom.vandenberghe@uantwerp.be.; VIB-UGent Center for Inflammation Research, Ghent, Belgium. tom.vandenberghe@uantwerp.be.; Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium. tom.vandenberghe@uantwerp.be.
Jazyk: angličtina
Zdroj: Cell death and differentiation [Cell Death Differ] 2024 Sep; Vol. 31 (9), pp. 1113-1126. Date of Electronic Publication: 2024 Jul 26.
DOI: 10.1038/s41418-024-01348-9
Abstrakt: There is an unmet clinical need for pharmacologic treatment for metabolic dysfunction-associated steatotic liver disease (MASLD). Hepatocyte cell death is a hallmark of this highly prevalent chronic liver disease, but the dominant type of cell death remains uncertain. Here we report that ferroptosis, an iron-catalyzed mode of regulated cell death, contributes to MASLD. Unsupervised clustering in a cohort of biopsy-proven MASLD patients revealed a subgroup with hepatic ferroptosis signature and lower glutathione peroxidase 4 (GPX4) levels. Likewise, a subgroup with reduced ferroptosis defenses was discerned in public transcriptomics datasets. Four weeks of choline-deficient L-amino acid-defined high-fat diet (CDAHFD) induced MASLD with ferroptosis in mice. Gpx4 overexpression did not affect steatohepatitis, instead CDAHFD protected from morbidity due to hepatocyte-specific Gpx4 knockout. The ferroptosis inhibitor UAMC-3203 attenuated steatosis and alanine aminotransferase in CDAHFD and a second model, i.e., the high-fat high-fructose diet (HFHFD). The effect of monounsaturated and saturated fatty acids supplementation on ferroptosis susceptibility was assessed in human HepG2 cells. Fat-laden HepG2 showed a drop in ferroptosis defenses, increased phosphatidylglycerol with two polyunsaturated fatty acid (PUFA) lipid tails, and sustained ferroptosis sensitivity. In conclusion, this study identified hepatic ferroptosis as a detrimental factor in MASLD patients. Unexpectedly, non-PUFA supplementation to hepatocytes altered lipid bilayer composition to maintain ferroptosis sensitivity. Based on findings in in vivo models, ferroptosis inhibition represents a promising therapeutic target in MASLD.
(© 2024. The Author(s).)
Databáze: MEDLINE
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