Targeting glutamine metabolism in hepatic stellate cells alleviates liver fibrosis

Abstract Glutamine metabolism plays an essential role in cell growth. Glutamate dehydrogenase (GDH) is a key enzyme in glutamine metabolism, promoting the metabolism of glutamate and glutamine and generating ATP, the level of which is profoundly increased in multiple human cancers. Through in vitro and in vivo experiments, we verified that the small-molecule GDH inhibitor EGCG slows the progression of fibrosis by inhibiting GDH enzyme activity and glutamine metabolism. SIRT4 is a mitochondrial enzyme that with NAD promotes ADP-ribosylation and downregulates GDH activity. The role played by 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) cycle, thereby reducing the proliferative activity of hepatic stellate cells (HSCs) and alleviating the development of liver fibrosis. Collectively, our study reveals that SIRT4 controls GDH enzyme activity and expression, regulating glutamine metabolism to activate HSCs growth.