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 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 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.

LAY SUMMARY:

We show that the enzyme carnitine palmitoyltransferase 1A (CPT1A) is elevated in hepatic stellate cells (HSCs) in patients with fibrosis and mouse models of fibrosis, and that CPT1A induces the activation of these cells. Inhibition of CPT1A ameliorates fibrosis by preventing the activation of HSCs.

• Authors: 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 López, Carlos 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
• Journal: Journal of hepatology (J Hepatol) Vol. 77 Issue 1 Pg. 15-28 (07 2022) ISSN: 1600-0641 [Electronic] Netherlands
• PMID: 35167910 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.

Chemical References

• Fatty Acids
• Carnitine O-Palmitoyltransferase
• Choline

Topics

• Animals
• Carnitine O-Palmitoyltransferase (genetics, metabolism)
• Choline
• Fatty Acids (metabolism)
• Fibrosis
• Hepatic Stellate Cells (metabolism)
• Humans
• Liver (pathology)
• Liver Cirrhosis (metabolism, prevention & control)
• Mice