Targeting glutamine metabolism in hepatic stellate cells alleviates liver fibrosis.
Cell Death Dis
; 13(11): 955, 2022 11 14.
Article
en En
| MEDLINE
| ID: mdl-36376267
ABSTRACT
Glutamine metabolism plays an essential role in cell growth, and glutamate dehydrogenase (GDH) is a key enzyme. GDH promotes the metabolism of glutamate and glutamine to generate ATP, which is profoundly increased in multiple human cancers. Through in vitro and in vivo experiments, we verified that the small-molecule GDH inhibitor EGCG slowed the progression of fibrosis by inhibiting GDH enzyme activity and glutamine metabolism. SIRT4 is a mitochondrial enzyme with NAD that promotes ADP ribosylation and downregulates GDH activity. The role of SIRT4 in liver fibrosis and the related mechanisms are unknown. In this study, we measured the expression of SIRT4 and found that it was downregulated in liver fibrosis. Modest overexpression of SIRT4 protected the liver from fibrosis by inhibiting the transformation of glutamate to 2-ketoglutaric acid (α-KG) in the tricarboxylic acid cycle (TCA), thereby reducing the proliferative activity of hepatic stellate cells (HSCs). Collectively, our study reveals that SIRT4 controls GDH enzyme activity and expression, targeting glutamine metabolism in HSCs and alleviating liver fibrosis.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Células Estrelladas Hepáticas
/
Glutamina
Límite:
Humans
Idioma:
En
Revista:
Cell Death Dis
Año:
2022
Tipo del documento:
Article
País de afiliación:
China