Inhibition of carnitine palmitoyl-transferase 1A in hepatic stellate cells protects against fibrosis

Marcos F Fondevila, Uxia Fernandez, Violeta Heras, Tamara Parracho, Maria J Gonzalez-Rellan, Eva Novoa, Begoña Porteiro, Cristina Alonso, Rebeca Mayo, Natalia da Silva Lima, Cristina Iglesias, Aveline A Filliol, Ana Senra, Teresa C Delgado, Ashwin Woodhoo, Laura Herrero, Dolors Serra, Vincent Prevot, Markus Schwaninger, Miguel LópezCarlos Dieguez, Oscar Millet, Jose M Mato, Francisco J Cubero, Marta Varela-Rey, Paula Iruzubieta, Javier Crespo, Maria L Martinez-Chantar, Robert F Schwabe, Ruben Nogueiras


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.

Original languageEnglish
JournalJournal of Hepatology
Issue number1
Pages (from-to)15-28
Number of pages14
Publication statusPublished - 07.2022


Dive into the research topics of 'Inhibition of carnitine palmitoyl-transferase 1A in hepatic stellate cells protects against fibrosis'. Together they form a unique fingerprint.

Cite this