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Intravascular hemolysis triggers NAFLD characterized by a deregulation of lipid metabolism and lipophagy blockade

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dc.contributor.author Rayego-Mateos, Sandra
dc.contributor.author Morgado Pascual, José Luis
dc.contributor.author García Caballero, Cristina
dc.contributor.author Lázaro, Iolanda
dc.contributor.author Sala Vila, Aleix
dc.contributor.author Opazo Ríos, Lucas
dc.contributor.author Mas Fontao, Sebastián
dc.contributor.author Egido, Jesús (Egido de los Ríos)
dc.contributor.author Ruiz Ortega, Marta
dc.contributor.author Moreno, Juan Antonio
dc.date.accessioned 2024-06-04T06:20:34Z
dc.date.available 2024-06-04T06:20:34Z
dc.date.issued 2023
dc.identifier.citation Rayego-Mateos S, Morgado-Pascual JL, García-Caballero C, Lazaro I, Sala-Vila A, Opazo-Rios L, et al. Intravascular hemolysis triggers NAFLD characterized by a deregulation of lipid metabolism and lipophagy blockade. J Pathol. 2023 Oct;261(2):169-83. DOI: 10.1002/path.6161
dc.identifier.issn 0022-3417
dc.identifier.uri http://hdl.handle.net/10230/60335
dc.description.abstract Intravascular hemolysis is a common feature of different clinical entities, including sickle cell disease and malaria. Chronic hemolytic disorders are associated with hepatic damage; however, it is unknown whether heme disturbs lipid metabolism and promotes liver steatosis, thereby favoring the progression to nonalcoholic fatty liver disease (NAFLD). Using an experimental model of acute intravascular hemolysis, we report here the presence of liver injury in association with microvesicular lipid droplet deposition. Hemolysis promoted serum hyperlipidemia and altered intrahepatic triglyceride fatty acid composition, with increments in oleic, palmitoleic, and palmitic acids. These findings were related to augmented expression of transporters involved in fatty acid uptake (CD36 and MSR1) and deregulation of LDL transport, as demonstrated by decreased levels of LDL receptor and increased PCSK9 expression. Hemolysis also upregulated hepatic enzymes associated with cholesterol biosynthesis (SREBP2, HMGC1, LCAT, SOAT1) and transcription factors regulating lipid metabolism (SREBP1). Increased LC3II/LC3I ratio and p62/SQSTM1 protein levels were reported in mice with intravascular hemolysis and hepatocytes stimulated with heme, indicating a blockade of lipophagy. In cultured hepatocytes, cell pretreatment with the autophagy inductor rapamycin diminished heme-mediated toxicity and accumulation of lipid droplets. In conclusion, intravascular hemolysis enhances liver damage by exacerbating lipid accumulation and blocking the lipophagy pathway, thereby promoting NAFLD. These new findings have a high translational potential as a novel NAFLD-promoting mechanism in individuals suffering from severe hemolysis episodes. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
dc.format.mimetype application/pdf
dc.language.iso eng
dc.publisher Wiley
dc.relation.ispartof J Pathol. 2023 Oct;261(2):169-83
dc.rights © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License (http://creativecommons.org/licenses/by-nc-nd/4.0/), which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
dc.rights.uri http://creativecommons.org/licenses/by-nc-nd/4.0/
dc.title Intravascular hemolysis triggers NAFLD characterized by a deregulation of lipid metabolism and lipophagy blockade
dc.type info:eu-repo/semantics/article
dc.identifier.doi http://dx.doi.org/10.1002/path.6161
dc.subject.keyword NAFLD
dc.subject.keyword Heme
dc.subject.keyword Intravascular hemolysis
dc.subject.keyword Lipid accumulation
dc.subject.keyword Lipid metabolism
dc.subject.keyword Lipophagy
dc.subject.keyword Liver damage
dc.rights.accessRights info:eu-repo/semantics/openAccess
dc.type.version info:eu-repo/semantics/publishedVersion

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