TRAP-seq identifies cystine/glutamate antiporter as a driver of recovery from liver injury.
J Clin Invest
; 128(6): 2297-2309, 2018 06 01.
Article
en En
| MEDLINE
| ID: mdl-29517978
Understanding the molecular basis of the regenerative response following hepatic injury holds promise for improved treatment of liver diseases. Here, we report an innovative method to profile gene expression specifically in the hepatocytes that regenerate the liver following toxic injury. We used the Fah-/- mouse, a model of hereditary tyrosinemia, which conditionally undergoes severe liver injury unless fumarylacetoacetate hydrolase (FAH) expression is reconstituted ectopically. We used translating ribosome affinity purification followed by high-throughput RNA sequencing (TRAP-seq) to isolate mRNAs specific to repopulating hepatocytes. We uncovered upstream regulators and important signaling pathways that are highly enriched in genes changed in regenerating hepatocytes. Specifically, we found that glutathione metabolism, particularly the gene Slc7a11 encoding the cystine/glutamate antiporter (xCT), is massively upregulated during liver regeneration. Furthermore, we show that Slc7a11 overexpression in hepatocytes enhances, and its suppression inhibits, repopulation following toxic injury. TRAP-seq allows cell type-specific expression profiling in repopulating hepatocytes and identified xCT, a factor that supports antioxidant responses during liver regeneration. xCT has potential as a therapeutic target for enhancing liver regeneration in response to liver injury.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Tirosinemias
/
Hepatocitos
/
Sistema de Transporte de Aminoácidos y/
/
Hígado
/
Regeneración Hepática
Tipo de estudio:
Prognostic_studies
Límite:
Animals
Idioma:
En
Revista:
J Clin Invest
Año:
2018
Tipo del documento:
Article
Pais de publicación:
Estados Unidos