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Current Molecular Pharmacology

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ISSN (Print): 1874-4672
ISSN (Online): 1874-4702

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Research Article

DDR1-Induced Paracrine Factors of Hepatocytes Promote HSC Activation and Fibrosis Development

Author(s): Ying Meng, Tong Zhao, Tiyun Han, Huilin Chen, Zhengyi Zhang and Dekui Zhang*

Volume 17, 2024

Published on: 04 May, 2023

Article ID: e220223213911 Pages: 19

DOI: 10.2174/1874467216666230222124515

open_access

Abstract

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.

Keywords: Liver fibrosis, Discoidin domain receptor 1, Hepatocyte, Hepatic stellate cell, Conditioned medium, α-smooth muscle actin.

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