ω-3 PUFAs ameliorate liver fibrosis and inhibit hepatic stellate cells proliferation and activation by promoting YAP/TAZ degradation

Zhang, Kun; Chang, Yanan; Shi, Zhemin; Han, Xiaohui; Han, Yan; Yao, Qingbin; Hu, Zhimei; Cui, Hongmei; Zheng, Lemin; Han, Tao; Wang, Hong

doi:10.1038/srep30029

Cited by 53 publications

(55 citation statements)

References 51 publications

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“…They showed that blocking Hh signaling in HSCs inhibited activation of YAP, and deletion of YAP in HSCs suppressed Hh signaling, suggesting that Hh and YAP interact to maintain the MF-phenotype in HSCs. In addition, both Hh and YAP signaling were shown to be associated with TGFb in HSC activation and liver carcinogenesis [16,[62][63][64]. Compared with the 10% infection groups, a greater increase of TGFβ and αSMA protein in the 30% infection groups appears to have been promoted by enhanced YAP activity, suggesting the possibility that YAP accelerates HSC activation.…”

Section: Discussionmentioning

confidence: 90%

Blood-Stage Plasmodium Berghei ANKA Infection Promotes Hepatic Fibrosis by Enhancing Hedgehog Signaling in Mice

Kim

Wang

Lee

et al. 2018

Cell Physiol Biochem

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Background/Aims: Malaria is the most deadly parasitic infection in the world, resulting in damage to various organs, including the liver, of the infected organism; however, the mechanism causing this damage in the liver remains unclear. Liver fibrosis, a major characteristic of liver diseases, occurs in response to liver injury and is regulated by a complex network of signaling pathways. Hedgehog (Hh) signaling orchestrates a number of hepatic responses including hepatic fibrogenesis. Therefore, we investigated whether Hh signaling influenced the liver’s response to malarial infection. Methods: Eight-week-old male C57BL/6 mice inoculated with blood containing Plasmodium berghei ANKA (PbA)-infected erythrocytes were sacrificed when the level of parasitemia in the blood reached 10% or 30%, and the livers were collected for biochemical analysis. Liver responses to PbA infection were examined by hematoxylin and eosin staining, real-time polymerase chain reaction, immunohistochemistry and western blot. Results: Severe hepatic injury, such as ballooned hepatocytes, sinusoidal dilatation, and infiltrated leukocytes, was evident in the livers of the malaria-infected mice. Hypoxia was also induced in 30% parasitemia group. With the accumulation of Kupffer cells, inflammation markers, TNF-α, interleukin-1β, and chemokine (C-X-C motif) ligand 1, were significantly upregulated in the infected group compared with the control group. Expression of fibrotic markers, including transforming growth factor-β, α-smooth muscle actin (α-SMA), collagen 1a1, thymosin β4, and vimentin, were significantly higher in the infected groups than in the control group. With increased collagen deposition, hepatic stellate cells expressing α-SMA accumulated in the liver of the PbA-infected mice, whereas those cells were rarely detected in the livers of the control mice. The levels of Hh signaling and Yes-associated protein (YAP), two key regulators for hepatic fibrogenesis, were significantly elevated in the infected groups compared with the control group. Treatment of mice with Hh inhibitor, GDC-0449, reduced hepatic inflammation and fibrogenesis with Hh suppression in PbA-infected mice. Conclusion: Our results demonstrate that HSCs are activated in and Hh and YAP signaling are associated with this process, contributing to increased hepatic fibrosis in malaria-infected livers.

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Section: Discussionmentioning

confidence: 90%

Blood-Stage Plasmodium Berghei ANKA Infection Promotes Hepatic Fibrosis by Enhancing Hedgehog Signaling in Mice

Kim

Wang

Lee

et al. 2018

Cell Physiol Biochem

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“…So, our findings support the notion that TAZ localization could play a significant role in the causation of liver cirrhosis. Speculatively, an increase in the levels of TAZ may represent a posttranscriptional mechanism, because there was no significant difference in the expression of WWTR1 mRNA between cirrhotic and control I subjects . Also, other probable reasons for this observation might be the differences in the in vivo half‐lives of TAZ or a possible error in both protein and mRNA experiments .…”

Section: Discussionmentioning

confidence: 98%

Liver stiffness correlates with serum osteopontin and TAZ expression in human liver cirrhosis

Khajehahmadi

Mohagheghi

Nikeghbalian

et al. 2019

Annals of the New York Academy of Sciences

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The pivotal role of the extracellular matrix (ECM) as both a cause and consequence of liver fibrosis is striking. However, mechanotransducer molecules and profibrogenic factors induced by liver stiffness are still unclear. The current study aimed to investigate liver stiffness and its correlation with the expression of the transcriptional coactivator with PDZ‐binding motif (TAZ) and serum osteopontin (OPN) in human cirrhosis. In this case−control study, liver tissue stiffness was determined using atomic force microscopy in cirrhotic livers (n = 38) of different etiologies and in controls (n = 10). Immunohistochemical and qRT‐PCR analyses were performed to analyze TAZ expression. Besides, western blotting and ELISA were performed to assess liver Indian hedgehog and serum OPN levels, respectively. Liver stiffness, TAZ expression, and hepatic gene expression and serum protein levels of OPN were significantly increased in patients with cirrhosis compared with the control groups (all P < 0.001), specifically in autoimmune‐ and alcohol‐related cirrhosis. In cirrhotic patients, liver stiffness was significantly associated with the expression of nuclear TAZ and OPN. The correlation between matrix stiffness as a mechanical property, TAZ as a potential mechanotransducer, and OPN as a matricellular factor suggests possible effects of mechanical features of the ECM on the expression of the aforementioned profibrogenic markers, which is predominant in autoimmune‐ and alcohol‐related cirrhosis.

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“…Fibrosis ending with cirrhosis as an architectural distortion occurs as sequence of persistent parenchymal damage and chronic hepatic stellate cell activation. YAP and TAZ played a major role as early key transcriptional effectors in HSCs (19,49). YAP can mediate epithelial mesenchymal transition in hepatocytes as one of fibrosis mechanisms in the liver (20,50).…”

Section: Discussionmentioning

confidence: 99%

Relation between immunohistochemical expression of hippo pathway effectors and chronic hepatitis induced fibrosis in egyptian patients

Abdallah

Shaban²,

Taie³

et al. 2019

TJPATH

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Objective: Chronic hepatitis is a global health problem especially in Egypt. Hepatic fibrosis is a common end clinical manifestation of many chronic liver diseases. Although it is a wound-healing process, excessive accumulation of fibrillary collagen leads to architectural damage, cirrhosis and liver failure. Recently, a few studies have linked Hippo pathway effectors of yes-associated protein (YAP) and its paralog transcriptional coactivator with PDZ-binding motif (TAZ) to extracellular matrix deposition and ongoing fibrosis. Material and Method:Immunohistochemical expression of YAP and TAZ were analyzed in 121 liver needle core biopsies (91 core biopsies of chronic viral hepatitis, 20 biopsies of autoimmune hepatitis and 10 normal liver cores).Results: YAP and TAZ nuclear localization was absent in all normal liver cores. Autoimmune hepatitis cases showed higher nuclear expression of both YAP and TAZ in comparison to chronic viral cases. YAP and TAZ expression were correlated with severity of hepatocyte injury together with fibrosis in chronic viral cases but these correlations were absent in AIH cases despite the pronounced increase of YAP and TAZ nuclear localization. Conclusion:The correlation between Hippo effectors activation and fibrosis in chronic viral hepatitis patients emphasize their role in the development and advancement of hepatic scarring and highlight the use of both YAP and TAZ as novel targets to ameliorate liver fibrosis.

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ω-3 PUFAs ameliorate liver fibrosis and inhibit hepatic stellate cells proliferation and activation by promoting YAP/TAZ degradation

Cited by 53 publications

References 51 publications

Blood-Stage Plasmodium Berghei ANKA Infection Promotes Hepatic Fibrosis by Enhancing Hedgehog Signaling in Mice

Blood-Stage Plasmodium Berghei ANKA Infection Promotes Hepatic Fibrosis by Enhancing Hedgehog Signaling in Mice

Liver stiffness correlates with serum osteopontin and TAZ expression in human liver cirrhosis

Relation between immunohistochemical expression of hippo pathway effectors and chronic hepatitis induced fibrosis in egyptian patients

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