Por favor, use este identificador para citar o enlazar a este item:
http://hdl.handle.net/10261/148503
COMPARTIR / EXPORTAR:
SHARE CORE BASE | |
Visualizar otros formatos: MARC | Dublin Core | RDF | ORE | MODS | METS | DIDL | DATACITE | |
Título: | Myristic acid potentiates palmitic acid-induced lipotoxicity and steatohepatitis associated with lipodystrophy by sustaning de novo ceramide synthesis |
Autor: | Martínez, Laura CSIC; Torres, Sandra CSIC ORCID; Baulies, Anna CSIC ORCID; Alarcón-Vila, Cristina CSIC ORCID; Elena, Montserrat; Fabriàs, Gemma CSIC ORCID ; Casas, Josefina CSIC ORCID ; Fernández-Checa, José C. CSIC ORCID; García-Ruiz, Carmen CSIC ORCID | Palabras clave: | Pathology Section NAFLD Endoplasmic reticulum Sphingolipid Hepatocyte FFA |
Fecha de publicación: | 2-nov-2015 | Editor: | Impact Journals | Citación: | Oncotarget 6: 41479- 41496 (2015) | Resumen: | Palmitic acid (PA) induces hepatocyte apoptosis and fuels de novo ceramide synthesis in the endoplasmic reticulum (ER). Myristic acid (MA), a free fatty acid highly abundant in copra/palmist oils, is a predictor of nonalcoholic steatohepatitis (NASH) and stimulates ceramide synthesis. Here we investigated the synergism between MA and PA in ceramide synthesis, ER stress, lipotoxicity and NASH. Unlike PA, MA is not lipotoxic but potentiated PA-mediated lipoapoptosis, ER stress, caspase-3 activation and cytochrome c release in primary mouse hepatocytes (PMH). Moreover, MA kinetically sustained PA-induced total ceramide content by stimulating dehydroceramide desaturase and switched the ceramide profile from decreased to increased ceramide 14:0/ceramide16:0, without changing medium and long-chain ceramide species. PMH were more sensitive to equimolar ceramide14:0/ceramide16:0 exposure, which mimics the outcome of PA plus MA treatment on ceramide homeostasis, than to either ceramide alone. Treatment with myriocin to inhibit ceramide synthesis and tauroursodeoxycholic acid to prevent ER stress ameliorated PA plus MA induced apoptosis, similar to the protection afforded by the antioxidant BHA, the pan-caspase inhibitor z-VAD-Fmk and JNK inhibition. Moreover, ruthenium red protected PMH against PA and MA-induced cell death. Recapitulating in vitro findings, mice fed a diet enriched in PA plus MA exhibited lipodystrophy, hepatosplenomegaly, increased liver ceramide content and cholesterol levels, ER stress, liver damage, inflammation and fibrosis compared to mice fed diets enriched in PA or MA alone. The deleterious effects of PA plus MA-enriched diet were largely prevented by in vivo myriocin treatment. These findings indicate a causal link between ceramide synthesis and ER stress in lipotoxicity, and imply that the consumption of diets enriched in MA and PA can cause NASH associated with lipodystrophy. | Versión del editor: | https://doi.org/10.18632/oncotarget.6286 | URI: | http://hdl.handle.net/10261/148503 | DOI: | 10.18632/oncotarget.6286 | Identificadores: | doi: 10.18632/oncotarget.6286 issn: 1949-2553 |
Aparece en las colecciones: | (IQAC) Artículos (IIBB) Artículos |
Ficheros en este ítem:
Fichero | Descripción | Tamaño | Formato | |
---|---|---|---|---|
Myristic acid potentiates-Martinez.pdf | 21,51 MB | Adobe PDF | Visualizar/Abrir |
CORE Recommender
PubMed Central
Citations
37
checked on 01-abr-2024
SCOPUSTM
Citations
76
checked on 17-abr-2024
WEB OF SCIENCETM
Citations
68
checked on 28-feb-2024
Page view(s)
362
checked on 23-abr-2024
Download(s)
224
checked on 23-abr-2024