DDR1-Induced Paracrine Factors of Hepatocytes Promote HSC Activation and Fibrosis Development
Copyright© Bentham Science Publishers; For any queries, please email at epubbenthamscience.net..
BACKGROUND: This study investigated the role and potential mechanisms of Discoidin domain receptors-1 (DDR1) during liver fibrogenesis.
METHODS: Blood and livers were collected from mice. In the in vitro experiments, human normal hepatocyte (LO2 cell line) and human hepatoma cells (HepG2 cell line) with overexpressed DDR1 (DDR1-OE) or DDR1 knockdown (DDR1-KD) were constructed by transfecting the corresponding lentivirus. Human hepatic stellate cells (LX2 cell line) were incubated with a conditioned medium (CM) of the above stable transfected cells treated with collagen. The cells and supernatants were collected for molecular and biochemical analyses.
RESULTS: DDR1 expression was increased in hepatocytes from carbon tetrachloride (CCL4)-induced fibrotic livers compared to normal livers in wild-type (WT) mice. Liver fibrosis was relieved, and hepatic stellate cells (HSC) activation was decreased in CCL4-treated DDR1 knockout (DDR1-KO) mice compared with CCL4-treated WT mice. LX2 cells cultured in CM of LO2 DDR1-OE cells revealed increased α-smooth muscle actin (αSMA) and type I collagen (COL1) expressions and cell proliferation. Meanwhile, cell proliferation and the expression levels of αSMA and COL1 in LX2 cells cultured in CM of HepG2 DDR1-KD cells were decreased. Moreover, IL6, TNFα, and TGFβ1 in CM of DDR1-OE cells appeared to promote LX2 cell activation and proliferation, regulated by NF-κB and Akt pathways.
CONCLUSION: These results indicated that DDR1 in hepatocytes promoted HSC activation and proliferation and that paracrine factors IL6, TNFα, and TGFβ1 induced by DDR1 through activating NF-κB and Akt pathways may be the underlying mechanisms. Our study suggests that collagen-receptor DDR1 may be a potential therapeutic target for hepatic fibrosis.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2024 2023 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:17 |
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| Enthalten in: |
Current molecular pharmacology - 17(2023), 1 vom: 21., Seite e220223213911 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Meng, Ying [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 27.11.2023 Date Revised 27.11.2023 published: Print Citation Status MEDLINE |
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| doi: |
10.2174/1874467216666230222124515 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM353163074 |
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| 500 | |a published: Print | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright© Bentham Science Publishers; For any queries, please email at epubbenthamscience.net. | ||
| 520 | |a BACKGROUND: This study investigated the role and potential mechanisms of Discoidin domain receptors-1 (DDR1) during liver fibrogenesis | ||
| 520 | |a METHODS: Blood and livers were collected from mice. In the in vitro experiments, human normal hepatocyte (LO2 cell line) and human hepatoma cells (HepG2 cell line) with overexpressed DDR1 (DDR1-OE) or DDR1 knockdown (DDR1-KD) were constructed by transfecting the corresponding lentivirus. Human hepatic stellate cells (LX2 cell line) were incubated with a conditioned medium (CM) of the above stable transfected cells treated with collagen. The cells and supernatants were collected for molecular and biochemical analyses | ||
| 520 | |a RESULTS: DDR1 expression was increased in hepatocytes from carbon tetrachloride (CCL4)-induced fibrotic livers compared to normal livers in wild-type (WT) mice. Liver fibrosis was relieved, and hepatic stellate cells (HSC) activation was decreased in CCL4-treated DDR1 knockout (DDR1-KO) mice compared with CCL4-treated WT mice. LX2 cells cultured in CM of LO2 DDR1-OE cells revealed increased α-smooth muscle actin (αSMA) and type I collagen (COL1) expressions and cell proliferation. Meanwhile, cell proliferation and the expression levels of αSMA and COL1 in LX2 cells cultured in CM of HepG2 DDR1-KD cells were decreased. Moreover, IL6, TNFα, and TGFβ1 in CM of DDR1-OE cells appeared to promote LX2 cell activation and proliferation, regulated by NF-κB and Akt pathways | ||
| 520 | |a CONCLUSION: These results indicated that DDR1 in hepatocytes promoted HSC activation and proliferation and that paracrine factors IL6, TNFα, and TGFβ1 induced by DDR1 through activating NF-κB and Akt pathways may be the underlying mechanisms. Our study suggests that collagen-receptor DDR1 may be a potential therapeutic target for hepatic fibrosis | ||
| 650 | 4 | |a Journal Article | |
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| 650 | 4 | |a Discoidin domain receptor 1 | |
| 650 | 4 | |a Hepatic stellate cell | |
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| 650 | 4 | |a Liver fibrosis | |
| 650 | 4 | |a α-smooth muscle actin. | |
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| 700 | 1 | |a Han, Tiyun |e verfasserin |4 aut | |
| 700 | 1 | |a Chen, Huilin |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Zhengyi |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Dekui |e verfasserin |4 aut | |
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