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

https://doi.org/10.1016/j.jhep.2022.02.003Get rights and content
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open access

Highlights

  • CPT1A is overexpressed in HSCs from patients with fibrosis and positively correlates with fibrosis and NAFLD activity score.

  • Fatty acid oxidation is increased in activated HSCs and CPT1A inhibition blunts HSC activation by reducing mitochondrial activity.

  • In experimental models, CPT1A-induced fibrogenesis is dependent on ATP availability.

  • The specific deletion of CPT1A in mouse HSCs protects against fibrosis.

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.

Keywords

CPT1A
NASH
fibrosis
metabolism
fatty acids
beta oxidation

Cited by (0)

Author names in bold designate shared co-first authorship

UF and VH contributed equally