Ferroptosis is a targetable detrimental factor in metabolic dysfunction-associated steatotic liver disease
Rattachement africain : be, jp. Niveau de preuve : code pays fourni par la source.
Le résumé fourni par la source
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.
Ce résumé expose les affirmations des auteurs. BNTIC ne l’interprète pas comme une validation indépendante des résultats.
Le contrôle bibliographique ouvert
DOI retrouvé dans Crossref DOI retrouvé ; titre concordant.
- Titre Crossref
- Ferroptosis is a targetable detrimental factor in metabolic dysfunction-associated steatotic liver disease
- Date Crossref
- 26/07/2024
- Éditeur
- Springer Science and Business Media LLC
- Type
- journal-article
Ce recoupement confirme des métadonnées liées au DOI. Il ne confirme ni la méthode ni les conclusions de l’étude, et il ne compte pas comme une seconde source scientifique indépendante.
Où se fait cette recherche
-
University of Antwerp Cell Death Signaling Lab pays non établi dans la noticeUniversité ou école supérieure
-
Antwerp University Hospital Department of Gastroenterology and Hepatology pays non établi dans la noticeOrganisme public
-
Nagoya University Department of Pathology and Biological Responses pays non établi dans la noticeUniversité ou école supérieure
-
VIB-UGent Center for Inflammation Research pays non établi dans la noticeStructure de recherche
-
Ghent University Department of Biomedical Molecular Biology pays non établi dans la noticeUniversité ou école supérieure
-
Faculty of Medicine and Health Sciences Department of ASTARC pays non établi dans la noticeUniversité ou école supérieure
Cell Death Signaling Lab — University of Antwerp, Department of Gastroenterology and Hepatology — Antwerp University Hospital et Department of Pathology and Biological Responses — Nagoya University, avec 3 autres affiliations.
Une affiliation ne permet pas de déduire la nationalité d’un auteur.