Targeting glutamine metabolism in hepatic stellate cells alleviates liver fibrosis

被引：39

作者：

Yin, Xiaochun ^{[1
]}

Peng, Jin ^{[2
]}

Gu, Lihong ^{[1
]}

Liu, Yan ^{[1
]}

Li, Xihan ^{[1
]}

Wu, Jinhui ^{[3
,4
]}

Xu, Bing ^{[1
]}

Zhuge, Yuzheng ^{[1
]}

Zhang, Feng ^{[1
]}

机构：

[1] Nanjing Univ Med Sch, Affiliated Hosp, Nanjing Drum Tower Hosp, Dept Gastroenterol, Nanjing, Jiangsu, Peoples R China

[2] Nanjing Univ, Med Sch, Affiliated Drum Tower Hosp, Hepatobiliary & Pancreat Ctr & Liver Transplantat, Nanjing, Peoples R China

[3] Nanjing Univ, Chem & Biomed Innovat Ctr, Med Sch, State Key Lab Pharmaceut Biotechnol, Nanjing 210093, Peoples R China

[4] Nanjing Univ, Jiangsu Key Lab Nano Technol, Nanjing 210093, Peoples R China

来源：

CELL DEATH & DISEASE | 2022年 / 13卷 / 11期

基金：

中国国家自然科学基金;

关键词：

SIRTUIN; 4; PROMOTES;

D O I：

10.1038/s41419-022-05409-0

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

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 (alpha-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.

引用

页数：9

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