The metabolic shift of glutaminase 2 to glutaminase 1 promotes LGR5 + progenitor cell proliferation in liver cirrhosis
Abstract Background and aim Liver regeneration is impaired in end-stage liver disease characterized by advanced fibrosis and cirrhosis, where metabolic reprogramming is considered as a therapeutic target. The shift in glutaminolysis from liver-type Glutaminase 2 (GLS2) to kidney-type Glutaminase 1 (...
Saved in:
| Main Authors: | , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Springer
2025-06-01
|
| Series: | Cellular and Molecular Life Sciences |
| Subjects: | |
| Online Access: | https://doi.org/10.1007/s00018-025-05772-z |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| Summary: | Abstract Background and aim Liver regeneration is impaired in end-stage liver disease characterized by advanced fibrosis and cirrhosis, where metabolic reprogramming is considered as a therapeutic target. The shift in glutaminolysis from liver-type Glutaminase 2 (GLS2) to kidney-type Glutaminase 1 (GLS1) is crucial in different liver diseases, though its role in liver progenitor cell-mediated regeneration remains unclear. This study aimed to analyze the expression of glutamine-metabolizing enzymes in fibrotic human livers and investigate the role of GLS1 in LGR5+-progenitor cell expansion in liver regeneration. Methods Healthy and chronically diseased human liver tissue from patients with alcoholic liver disease, viral hepatitis, biliary atresia, primary biliary cholangitis or non-alcoholic steatohepatitis were immunostained for GLS1, GLS2 and glutamine synthetase (GS), and co-stained for LGR5. GLS1 was inhibited in adult progenitor cell-rived human liver organoids to evaluate its role in stemness and cell proliferation pathways. Results GLS1 expression was enhanced and GLS2 decreased in chronic liver diseases compared to healthy liver. GLS1 was expressed in parenchymal, including hepatocytes, and non-parenchymal cells. In cirrhotic livers, GLS1+ hepatocytes showed a spatial distribution comparable to the progenitor cell marker LGR5. The GLS1 inhibitor CB839 suppressed progenitor cell markers (LGR5 and AXIN2) via the ROS-Wnt/β-Catenin pathway, which was rescued by glutathione (GSH). The CB839-mediated decrease in cell proliferation in human liver organoids was rescued by non-essential amino acids. Conclusions This study identifies GLS1 as a metabolic regulator of progenitor cell expansion aiding liver regeneration in various etiologies of human liver cirrhosis. |
|---|---|
| ISSN: | 1420-9071 |