RGD Reference Report - Regulation of hepatic stellate cell proliferation and activation by glutamine metabolism. - Rat Genome Database
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Regulation of hepatic stellate cell proliferation and activation by glutamine metabolism.

Authors: Li, Jiang  Ghazwani, Mohammed  Liu, Ke  Huang, Yixian  Chang, Na  Fan, Jie  He, Fengtian  Li, Liying  Bu, Shizhong  Xie, Wen  Ma, Xiaochao  Li, Song 
Citation: Li J, etal., PLoS One. 2017 Aug 10;12(8):e0182679. doi: 10.1371/journal.pone.0182679. eCollection 2017.
RGD ID: 13504826
Pubmed: (View Article at PubMed) PMID:28797105
DOI: Full-text: DOI:10.1371/journal.pone.0182679

Liver fibrosis is the excessive accumulation of extracellular matrix proteins, which is mainly caused by accumulation of activated hepatic stellate cells (HSCs). The mechanisms of activation and proliferation of HSCs, two key events after liver damage, have been studied for many years. Here we report a novel pathway to control HSCs by regulating glutamine metabolism. We demonstrated that the proliferation of HSCs is critically dependent on glutamine that is used to generate α-ketoglutarate (α-KG) and non-essential amino acid (NEAA). In addition, both culture- and in vivo-activated HSCs have increased glutamine utilization and increased expression of genes related to glutamine metabolism, including GLS (glutaminase), aspartate transaminase (GOT1) and glutamate dehydrogenase (GLUD1). Inhibition of these enzymes, as well as glutamine depletion, had a significant inhibitory effect on HSCs activation. In addition to providing energy expenditure, conversion of glutamine to proline is enhanced. The pool of free proline may also be increased via downregulation of POX expression. Hedgehog signaling plays an important role in the regulation of glutamine metabolism, as well as TGF-ß1, c-Myc, and Ras signalings, via transcriptional upregulation and repression of key metabolic enzymes in this pathway. Finally, changes in glutamine metabolism were also found in mouse liver tissue following CCl4-induced acute injury.
CONCLUSION: Glutamine metabolism plays an important role in regulating the proliferation and activation of HSCs. Strategies that are targeted at glutamine metabolism may represent a novel therapeutic approach to the treatment of liver fibrosis.

Annotation

Gene Ontology Annotations    

Biological Process

Objects Annotated

Genes (Rattus norvegicus)
Got1  (glutamic-oxaloacetic transaminase 1)


Additional Information