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Inhibition of carnitine palmitoyltransferase 1A in hepatic stellate cells protects against fibrosis

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

Autoría

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