Thioacetamide-Induced Norepinephrine Production by Hepatocytes is Associated with Hepatic Stellate Cell Activation and Liver Fibrosis
| Autor: | Keane K Y Lai, Keith Lai, Wendong Huang, Ya-Wen Chang, Shwu-Bin Lin, Patrick T. Fueger, Mei-Hui Wang, Wei-Chien Tang, Mingtian Che |
|---|---|
| Rok vydání: | 2022 |
| Předmět: |
Liver Cirrhosis
medicine.medical_specialty Hepatotoxin General Medicine Thioacetamide medicine.disease_cause Hepatic stellate cell activation Mice Norepinephrine chemistry.chemical_compound Paracrine signalling medicine.anatomical_structure Endocrinology chemistry Cell culture Culture Media Conditioned Hepatocyte Internal medicine Hepatic Stellate Cells Hepatocytes medicine Hepatic stellate cell Animals Oxidative stress |
| Zdroj: | Current Molecular Pharmacology. 15:454-461 |
| ISSN: | 1874-4672 |
| DOI: | 10.2174/1874467214666210412144416 |
| Popis: | Background: Collagen production by activated hepatic stellate cells (HSCs) to encapsulate injury is part of the natural wound-healing response in injured liver. However, persistent activation of HSCs can lead to pathological fibrogenesis. Such persistent HSC activation could be mediated by norepinephrine (NE), a reaction product of dopamine beta-hydroxylase (DBH). Objective: To investigate the potential paracrine role of NE in hepatotoxin thioacetamide (TAA)-induced liver fibrosis. Methods: In TAA-treated mice, fibrotic liver tissue showed significant increases in the mRNA expression of DBH up to 14-fold and collagen up to 7-fold. Immunohistochemical staining showed increased DBH protein expression in fibrotic liver tissue. Parenchymal hepatocyte cell line HepG2 expressed DBH and secreted NE, and the conditioned medium of HepG2 cells promoted collagenesis in nonparenchymal HSC cell line LX-2. TAA treatment increased DBH expression by 170% in HepG2 cells, as well as increased NE by 120% in the conditioned medium of HepG2 cells. The conditioned medium of TAA-treated HepG2 cells was used to culture LX-2 cells, and was found to increase collagen expression by 80% in LX-2 cells. Collagen expression was reduced by pre-treating HepG2 cells with siRNA targeting DBH or by adding NE antagonists to the conditioned medium. Results: Finally, TAA-induced oxidative stress in HepG2 cells was associated with induction of DBH expression. Collectively, our results suggest a potential role for DBH/NE-mediated crosstalk between hepatocytes and HSCs in fibrogenesis. Conclusion: From a therapeutic standpoint, antagonism of DBH/NE induction in hepatocytes might be a useful strategy to suppress pathological fibrogenesis. |
| Databáze: | OpenAIRE |
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