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http://hdl.handle.net/2445/184394
Title: | Inhibition of carnitine palmitoyl-transferase 1A in hepatic stellate cells protects against fibrosis |
Author: | Fondevila, Marcos F. Fernandez, Uxia Heras, Violeta Parracho, Tamara González-Rellan, Maria J. Novoa Pardo, Eva Maria Porteiro, Begoña Alonso, Cristina Mayo, Rebeca da Silva Lima, Natália Iglesias, Cristina Filliol, Aveline A. Senra, Ana Delgado, Teresa C. Woodhoo, Ashwin Herrero Rodríguez, Laura Serra i Cucurull, Dolors Prevot, Vincent Schwaninger, Markus López, Miguel Diéguez, Carlos Millet Aguilar-Galindo, Òscar Mato, José M. Cubero, Francisco Javier Varela Rey, Marta Iruzubieta, Paula Crespo, Javier Martínez Chantar, Maria Luz Schwabe, Robert F. Nogueiras, Rubén |
Keywords: | Metabolisme dels lípids Mitocondris Malalties del fetge Lipid metabolism Mitochondria Liver diseases |
Issue Date: | 2022 |
Publisher: | Elsevier |
Abstract: | Background & Aims The pathogenesis of liver fibrosis requires activation of hepatic stellate cells (HSCs); once activated, HSCs lose intracellular fatty acids but the role of fatty acid oxidation and carnitine palmitoyltransferase 1A (CPT1A) in this process remains largely unexplored. Methods CPT1A was found in HSCs of patients with fibrosis. Pharmacological and genetic manipulation of CPT1A were done in HSCs human cell lines and primary HCSs. Finally, we induced fibrosis in mice lacking CPT1A specifically in HSCs. Results Here we show that CPT1A expression is elevated in HSCs of patients with NASH, showing a positive correlation with the fibrosis score. This was corroborated in rodents with fibrosis, as well as in primary human HSCs and LX-2 cells activated by transforming growth factor β1 (TGFβ1) and fetal bovine serum (FBS). Furthermore, both pharmacological and genetic silencing of CPT1A prevent TGFβ1- and FBS-induced HSC activation by reducing mitochondrial activity. The overexpression of CPT1A, induced by saturated fatty acids and reactive oxygen species, triggers mitochondrial function and the expression of fibrogenic markers. Finally, mice lacking CPT1A specifically in HSCs are protected against fibrosis, induced by a choline-deficient high fat diet, a methionine- and choline-deficient diet, or treatment with carbon tetrachloride. Conclusions These results indicate that CPT1A plays a critical role in activation of HSCs and is implicated in the development of liver fibrosis, making it a potentially actionable target for fibrosis treatment. Lay summary We show that CPT1A located in HSCs is elevated in patients and mice models with fibrosis, and that CPT1A induces the activation of these cells. Inhibition of CPT1A ameliorates fibrosis by preventing the activation of HSCs. |
Note: | Versió postprint del document publicat a: https://doi.org/10.1016/j.jhep.2022.02.003 |
It is part of: | Journal of Hepatology, 2022 |
URI: | http://hdl.handle.net/2445/184394 |
Related resource: | https://doi.org/10.1016/j.jhep.2022.02.003 |
ISSN: | 0168-8278 |
Appears in Collections: | Articles publicats en revistes (Bioquímica i Fisiologia) |
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