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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 performed in human HSC cell lines and primary HCSs. Finally, we induced fibrosis in mice lacking CPT1A specifically in HSCs. Results Herein, we show that CPT1A expression is elevated in HSCs of patients with non-alcoholic steatohepatitis, 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 ?1 (TGF?1) and fetal bovine serum (FBS). Furthermore, both pharmacological and genetic silencing of CPT1A prevent TGF?1- and FBS-induced HSC activation by reducing mitochondrial activity. The overexpression of CPT1A, induced by saturated fatty acids and reactive oxygen species, triggers mitochondrial activity 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 the activation of HSCs and is implicated in the development of liver fibrosis, making it a potentially actionable target for fibrosis treatment.
Fuente: J Hepatol . 2022 Jul;77(1):15-28
Editorial: Elsevier
Año de publicación: 2022
Nº de páginas: 15
Tipo de publicación: Artículo de Revista
DOI: 10.1016/j.jhep.2022.02.003
ISSN: 0168-8278,1600-0641
Proyecto español: SAF2017-83813-C3-1-R; SAF2017-87301-R BFU2017-87721
Url de la publicación: https://doi.org/10.1016/j.jhep.2022.02.003
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FONDEVILA, MARCOS F.
FERNANDEZ, UXIA
HERAS, VIOLETA
PARRACHO, TAMARA
GONZALEZ-RELLAN, MARIA J.
NOVOA, EVA
PORTEIRO, BEGOÑA
ALONSO, CRISTINA
MAYO, REBECA
DA SILVA LIMA, NATALIA
IGLESIAS, CRISTINA
FILLIOL, AVELINE A.
SENRA, ANA
DELGADO, TERESA C.
WOODHOO, ASHWIN
HERRERO, LAURA
SERRA, DOLORS
PREVOT, VINCENT
PAULA IRUZUBIETA COZ
JAVIER CRESPO GARCIA
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