Abstract
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-β1, 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.
Highlights
Liver fibrosis is the result of chronic liver damage such as chronic HCV infection, alcohol abuse, and nonalcoholic steatohepatitis (NASH), which is characterized as an excessive accumulation of extracellular matrix (ECM) [1,2,3]
To further confirm the role of glutamine metabolism in Hepatic stellate cells (HSCs), we examined the inhibitory effects of glutaminase (GLS) inhibitor, Bptes, GLUD1 inhibitor, EGCG, and a pan inhibitor of transaminases inhibitor, AOAA on cell proliferation
In HSCs, the first report of metabolic changes during cell transactivation came from Dr Diehl’s group (24). They found that there were significant changes to glucose metabolism in A-HSCs compared with Q-HSCs
Summary
Liver fibrosis is the result of chronic liver damage such as chronic HCV infection, alcohol abuse, and nonalcoholic steatohepatitis (NASH), which is characterized as an excessive accumulation of extracellular matrix (ECM) [1,2,3]. HSCs were identified as the main collagen-producing cells in the liver after going through a sophisticated process of transactivation or transdifferentiation and becoming myofibroblast-like cells [9]. These activated HSCs acquire the ability to grow rapidly and produce large amounts of collagens, which are the major components of ECM [10, 11]. Glutamine (GLN), one of the nonessential amino acids, has important and unique metabolic functions. A few types of cancer cells have been shown to have addiction to increased GLN metabolism to fuel anabolic processes. Several important signaling pathways contribute to the regulation of glutamine metabolism in HSCs
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