2026-04-14T02:18:21Zhttps://recercat.cat/oai/request
oai:recercat.cat:2445/1843942025-12-04T22:55:11Zcom_2072_1057col_2072_478782col_2072_478917
RECERCAT author Fondevila, Marcos F. author Fernandez, Uxia author Heras, Violeta author Parracho, Tamara author González-Rellan, Maria J. author Novoa Pardo, Eva Maria author Porteiro, Begoña author Alonso, Cristina author Mayo, Rebeca author da Silva Lima, Natália author Iglesias, Cristina author Filliol, Aveline A. author Senra, Ana author Delgado, Teresa C. author Woodhoo, Ashwin author Herrero Rodríguez, Laura author Serra i Cucurull, Dolors author Prevot, Vincent author Schwaninger, Markus author López, Miguel author Diéguez, Carlos author Millet Aguilar-Galindo, Òscar author Mato, José M. author Cubero, Francisco Javier author Varela Rey, Marta author Iruzubieta, Paula author Crespo, Javier author Martínez Chantar, Maria Luz author Schwabe, Robert F. author Nogueiras, Rubén 2022-03-25T07:49:30Z2023-12-31T06:10:18Z20222022-03-25T07:49:30Z 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. cc-by-nc-nd (c) Elsevier, 2022 https://creativecommons.org/licenses/by-nc-nd/4.0/ info:eu-repo/semantics/openAccess Metabolisme dels lípids Mitocondris Malalties del fetge Lipid metabolism Mitochondria Liver diseases Inhibition of carnitine palmitoyl-transferase 1A in hepatic stellate cells protects against fibrosis info:eu-repo/semantics/article info:eu-repo/semantics/acceptedVersion