Therapeutic potential of targeting regulatory mechanisms of hepatic stellate cell activation in liver fibrosis

Baghaei, Kaveh; Mazhari, Sogol; Tokhanbigli, Samaneh; Parsamanesh, Gilda; Alavifard, Helia; Schaafsma, Dedmer; Ghavami, Saeid

doi:10.1016/j.drudis.2021.12.012

Cited by 47 publications

(30 citation statements)

References 149 publications

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“…In response to liver injury, they proliferate and transdifferentiate from a "quiescent" to an "activated" phenotype responsible for most of the ECM deposition in liver tissue, leading to liver fibrosis (Blaner et al, 2009;Friedman, 2000). HSCs communicate with immune cells, sinusoidal endothelial cells, and/or hepatocytes during liver pathophysiology via various growth factors, chemokines, and cytokines (Baghaei et al, 2022). Growth factors, including transforming growth factor (TGF)-β1, connective tissue growth factor, platelet-derived growth factor, and vascular endothelial growth factor, play essential roles in HSC activation.…”

Section: Introductionmentioning

confidence: 99%

“…Growth factors, including transforming growth factor (TGF)-β1, connective tissue growth factor, platelet-derived growth factor, and vascular endothelial growth factor, play essential roles in HSC activation. Among them, TGF-β1 induces HSC activation as a principal factor through signal transducers for receptors of the TGF-β superfamily-dependent or -independent pathways, resulting in upregulated expression of ECM components (Fabregat et al, 2016;Zhang, 2017;Baghaei et al, 2022). Inflammation is a major hallmark of liver fibrosis and is mediated by chemokines, which induce the chemotaxis of immune cells in the liver (Hellerbrand et al, 1998;Sahin et al, 2012;Lee et al, 2018b;Bartneck et al, 2021).…”

Section: Introductionmentioning

confidence: 99%

“…Therefore, chemokines regulate HSC activation and liver fibrosis progression. Various cell types release inflammatory cytokines during liver injury, promoting HSC activation and liver fibrosis (Baghaei et al, 2022). Multiple pro-inflammatory interleukins (IL), including IL-1β, regulate the biological function of liver-resident cells and induce the recruitment of immune cells to the liver (Gieling et al, 2009;Masola et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

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AKT regulates IL-1β-induced proliferation and activation of hepatic stellate cells

Yoon¹,

HWANG²,

SAIMA³

et al. 2023

Biocell

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Background: Activated hepatic stellate cells (HSCs) are closely involved in the initiation, perpetuation, and resolution of liver fibrosis. Pro-inflammatory cytokine levels are positively correlated with the transition from liver injury to fibrogenesis and contribute to HSC pathophysiology in liver fibrosis. Methods: In this study, we investigated the effect of the pro-inflammatory cytokine interleukin (IL)-1β on the proliferation and signaling pathways involved in fibrogenesis in LX-2 cells, an HSC cell line, using western blotting and cell proliferation assays. Results: IL-1β increased the proliferation rate and α-smooth muscle actin (SMA) expression of LX-2 cells in a dose-dependent manner. Within 1 h after IL-1β treatment, c-Jun N-terminal kinase (JNK), p38, and nuclear factor-κB (NF-κB) signaling was activated in LX-2 cells. Subsequently, protein kinase B (AKT) phosphorylation and an increase in α-SMA expression were observed in LX-2 cells. Each inhibitor of JNK, p38, or NF-κB decreased cell proliferation, AKT phosphorylation, and α-SMA expression in IL-1β-treated LX-2 cells. Conclusion: These results indicate that JNK, p38, and NF-κB signals converge at AKT phosphorylation, leading to LX-2 activation by IL-1β. Therefore, the AKT signaling pathway can be used as a target for alleviating liver fibrosis by the inflammatory cytokine IL-1β.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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AKT regulates IL-1β-induced proliferation and activation of hepatic stellate cells

Yoon¹,

HWANG²,

SAIMA³

et al. 2023

Biocell

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“…In the case of liver damage, HSCs are activated and produce ECM and many cytokines, as well as expressing α-smooth muscle actin (α-SMA) [4]. HSC phenotype transdifferentiation can be directed by transforming growth factor-β1 (TGF-β1), epidermal growth factor (EGF), platelet-derived growth factor (PDGF), and other cytokines [2,[5][6][7]. Emerging evidence suggest that inhibit HSC activation can effectively terminate or even cure LF [2,8] which could serve as a candidate of antifibrotic approach.…”

Section: Introductionmentioning

confidence: 99%

USP9X-mediated NRP1 deubiquitination promotes liver fibrosis by activating hepatic stellate cells

et al. 2023

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Liver fibrosis is a complex fibrotic process that develops early in the course of cirrhosis and is caused by chronic liver damage. The activation of hepatic stellate cells is primarily responsible for the fibrosis process. Studies show that NRP1 influences HSC motility and migration. However, whether NRP1 regulates HSC activation remains unknown. C57BL/6 male mice (6–8 weeks old) were intraperitoneally injected with 10% CCl4 in olive oil (5 μl/g body weight) every three days for four weeks to create an animal model of liver fibrosis. Control mice received olive oil (5 μl/g body weight). Different assays such as immunohistochemistry, immunostaining, Western blotting, qRT-PCR, immunoprecipitation, immunoprecipitation, and GST pull-down assays, and in vivo and in vitro ubiquitination assays were conducted. We found that NRP1 expression was significantly elevated both in mouse and human fibrotic livers, mainly in activated HSCs at the fibrotic foci. NRP1 promoted HSC activation via the cytokine TGF-β1, VEGFA, and PDGF-BB. Moreover, USP9X was found to be a critical deubiquitinating enzyme for the stability and high activity of NRP1 and NRP1 deubiquitination mediated by USP9X enhanced HSC activation and liver fibrosis. NRP1 deubiquitination mediated by USP9X enhances HSC activation, implying that targeting NRP1 or USP9X potentiates novel options in the treatment of liver fibrosis.

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“…Transforming growth factor-beta (Tgf-β) superfamily members has a crucial role in CNS development [ 15 ]. Based on the cell type, the developmental phase/time, and tissue location, may create several biological outcomes [ 16 ]. Furthermore, the TGF-β proteins prepare postural information for distinct progenitor cells by creating long-range concentration gradients, resulting in cell fate decisions and tissue patterning [ 17 , 18 ].…”

Section: Introductionmentioning

confidence: 99%

Potential role of TGFΒ and autophagy in early cerebellum development

Dalvand¹,

Rosa²,

Ghavami³

et al. 2022

Biochemistry and Biophysics Reports

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Therapeutic potential of targeting regulatory mechanisms of hepatic stellate cell activation in liver fibrosis

Cited by 47 publications

References 149 publications

AKT regulates IL-1β-induced proliferation and activation of hepatic stellate cells

AKT regulates IL-1β-induced proliferation and activation of hepatic stellate cells

USP9X-mediated NRP1 deubiquitination promotes liver fibrosis by activating hepatic stellate cells

Potential role of TGFΒ and autophagy in early cerebellum development

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