Targeting Endothelial Erk1/2-Akt Axis as a Regeneration Strategy to Bypass Fibrosis during Chronic Liver Injury in Mice

Lao, Yuanxiang; Li, Yanyan; Zhang, Ping; Shao, Qianqian; Lin, Weiran; Qiu, Bin; Lv, Yongzhuang; Tang, Lichun; Su, Shishuai; Zhang, Hongyu; Tian, Chunyan; Sun, Aihua; Huang, Wei; Zhang, Pumin; Wu, Yan; Jiang, Ying; He, Fuchu

doi:10.1016/j.ymthe.2018.08.016

Cited by 22 publications

(17 citation statements)

References 55 publications

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“…Erk1/2 expression was associated with preservation of a pro-regenerative phenotype of LSEC and HSC quiescence through NO regulation and controlling the antioxidant response, but also via increase of the mitogens HGF and Wnt2. Indeed, Akt upregulation provoked LSEC pro-fibrotic phenotype promoting HSC activation and reducing NO, HGF, and Wnt2 expression [218].…”

Section: Role Of Lsec Balancing Liver Regeneration and Fibrosismentioning

confidence: 99%

“…Furthermore, the polymer poly(maleic anhydride-alt-1-octadecene) has also been used to coat superparamagnetic iron oxide nanoparticles in order to direct them to the sinusoidal endothelium [272]. Besides that, adenovirus with the endothelial cell specific ROBO4 promoter have been seen to present a high degree of LSEC specificity and have been used to promote liver regeneration while bypassing fibrosis [218]. Finally, quantum dots (QDs), a type of nanoparticles with a size between 1-20 nm that present quantum effects [265] are also an area or interest [265].…”

Section: Lsec Targeting: Potential For Therapymentioning

confidence: 99%

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The Endothelium as a Driver of Liver Fibrosis and Regeneration

Lafoz

Ruart

Anton

et al. 2020

Cells

103

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Liver fibrosis is a common feature of sustained liver injury and represents a major public health problem worldwide. Fibrosis is an active research field and discoveries in the last years have contributed to the development of new antifibrotic drugs, although none of them have been approved yet. Liver sinusoidal endothelial cells (LSEC) are highly specialized endothelial cells localized at the interface between the blood and other liver cell types. They lack a basement membrane and display open channels (fenestrae), making them exceptionally permeable. LSEC are the first cells affected by any kind of liver injury orchestrating the liver response to damage. LSEC govern the regenerative process initiation, but aberrant LSEC activation in chronic liver injury induces fibrosis. LSEC are also main players in fibrosis resolution. They maintain liver homeostasis and keep hepatic stellate cell and Kupffer cell quiescence. After sustained hepatic injury, they lose their phenotype and protective properties, promoting angiogenesis and vasoconstriction and contributing to inflammation and fibrosis. Therefore, improving LSEC phenotype is a promising strategy to prevent liver injury progression and complications. This review focuses on changes occurring in LSEC after liver injury and their consequences on fibrosis progression, liver regeneration, and resolution. Finally, a synopsis of the available strategies for LSEC-specific targeting is provided.

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Section: Role Of Lsec Balancing Liver Regeneration and Fibrosismentioning

confidence: 99%

Section: Lsec Targeting: Potential For Therapymentioning

confidence: 99%

The Endothelium as a Driver of Liver Fibrosis and Regeneration

Lafoz

Ruart

Anton

et al. 2020

Cells

103

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“…Additionally, non-canonical Smad-independent signaling pathways such as PI3K/Akt are activated by TGFβ and provide a broad TGFβ-induced intracellular crosstalk [18,19]. Targeting PI3K/Akt signaling also restrains the progression of HSC activation, including cell proliferation and CTGF expression [34,35,[60][61][62], supporting the biological significance of the PI3K/Akt pathway for TGFβ-dependent HSC activation. In this study, BAY 41-2272 reduced the TGFβ1-induced phosphorylation of Akt but not canonical Smad2/3.…”

Section: Discussionmentioning

confidence: 87%

BAY 41-2272 Attenuates CTGF Expression via sGC/cGMP-Independent Pathway in TGFβ1-Activated Hepatic Stellate Cells

Chen

Kuo

et al. 2020

Biomedicines

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Activation of hepatic stellate cells (HSCs) is a critical pathogenic feature of liver fibrosis and cirrhosis. BAY 41-2272 is a canonical non-nitric oxide (NO)-based soluble guanylyl cyclase (sGC) stimulator that triggers cyclic guanosine monophosphate (cGMP) signaling for attenuation of fibrotic disorders; however, the impact of BAY 41-2272 on HSC activation remains ill-defined. Transforming growth factor (TGF)β and its downstream connective tissue growth factor (CTGF or cellular communication network factor 2, CCN2) are critical fibrogenic cytokines for accelerating HSC activation. Here, we identified that BAY 41-2272 significantly inhibited the TGFβ1-induced mRNA and protein expression of CTGF in mouse primary HSCs. Indeed, BAY 41-2272 increased the sGC activity and cGMP levels that were potentiated by two NO donors and inhibited by a specific sGC inhibitor, ODQ. Surprisingly, the inhibitory effects of BAY 41-2272 on CTGF expression were independent of the sGC/cGMP pathway in TGFβ1-activated primary HSCs. BAY 41-2272 selectively restricted the TGFβ1-induced phosphorylation of Akt but not canonical Smad2/3 in primary HSCs. Together, we illustrate a unique framework of BAY 41-2272 for inhibiting TGFβ1-induced CTGF upregulation and HSC activation via a noncanonical Akt-dependent but sGC/cGMP-independent pathway.

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“…On one hand, AKT activation improves hepatic regeneration, and is involved in restricting pro-inflammatory and promoting anti-inflammatory responses via negative regulation of TLR and NF-κB signaling in macrophages 55 ; on the other hand, PI3K/AKT pathway blockade in HSCs has been shown to suppress fibrotic responses by inhibiting HSCs proliferation and collagen synthesis 56 . Interestingly, the ERK-AKT axis has been suggested to act as a switch regulating liver regeneration or fibrosis via liver sinusoidal endothelial cells (LSECs)-HSCs communication 57 . Thus, the expected effect of Cpd17 through LPA-mediated signaling, is likely masked by the effect of other relevant regulatory pathways in the MAP/AKT signaling pathway which affect differentially different cell types in the liver.…”

Section: Discussionmentioning

confidence: 99%

A type IV Autotaxin inhibitor ameliorates acute liver injury and non-alcoholic steatohepatitis in mice

Booijink

Salgado-Polo

Jamieson

et al. 2022

Preprint

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An important but rather underexplored pathway implicated in liver disease is the lysophosphatidic acid (LPA) signaling axis. LPA acts through G-protein coupled receptors inducing downstream signaling pathways related to cell proliferation, differentiation, and migration, and is predominantly produced by the extracellular phosphodiesterase, Autotaxin (ATX). ATX has gained significant attention lately with an impressive number of ATX inhibitors (type I-IV) reported. Here, we aim to evaluate the therapeutic potential of a (yet unexplored) type IV ATX inhibitor, Cpd17, in liver injury. In this study, we first confirmed the involvement of the ATX/LPA signaling axis in human and murine diseased livers. Thereafter, we evaluated the effects of Cpd17, in comparison with the classic type I ATX inhibitor PF8380, in vitro. While both inhibitors attenuated induced cell injury phenotypes as assessed using various assays and specific readout parameters in hepatocytes, macrophages, and hepatic stellate cells (HSCs), Cpd17 appeared more effective. This prompted us to characterize the mechanism of action of both inhibitors in situ and in vitro in macrophages and HSCs, demonstrating that Cpd17 was more potent in inhibiting relevant signaling pathways, namely RhoA-mediated cytoskeletal remodeling, and phosphorylation of MAPK/ERK and AKT/PKB. Finally, we investigated the therapeutic potential of Cpd17 in two liver disease mouse models, CCl4-induced acute liver injury and diet-induced non-alcoholic steatohepatitis. We demonstrate that Cpd17 has an excellent potential for reducing liver injury in both disease models in vivo. We conclude that ATX inhibition, by type IV inhibitor in particular, has an excellent potential for clinical application in liver diseases.

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Targeting Endothelial Erk1/2-Akt Axis as a Regeneration Strategy to Bypass Fibrosis during Chronic Liver Injury in Mice

Cited by 22 publications

References 55 publications

The Endothelium as a Driver of Liver Fibrosis and Regeneration

The Endothelium as a Driver of Liver Fibrosis and Regeneration

BAY 41-2272 Attenuates CTGF Expression via sGC/cGMP-Independent Pathway in TGFβ1-Activated Hepatic Stellate Cells

A type IV Autotaxin inhibitor ameliorates acute liver injury and non-alcoholic steatohepatitis in mice

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