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 56 publications

(58 citation statements)

References 51 publications

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“…In the current study, combined with the significant decrease in collagen fibers demonstrated in Masson trichrome stain (F2), there was a significant reduction in α-SMA and TIMP-1 expression in group III as compared to that in group II. In line with our results, Zhang et al 2016 [36] reported that omega-3 fatty acids down-regulate the expression of profibrogenic genes in activated HSCs by inducing degradation of their transcriptional regulator; Yes-associated protein (YAP) in a proteasome dependent manner. In addition, omega-3 fatty acids exerted a potent anti-fibrotic effect in the models of cardiac and pulmonary fibrosis [37,38] .…”

Section: Discussionsupporting

confidence: 92%

Impact of omega-3 fatty acids on evolution of carbon tetrachloride- (CCl4) induced liver cirrhosis in mice : A histological and immunohistochemical study

Abu-Dief

Mohammed

El-Haliem

et al. 2018

Egyptian Journal of Histology

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Introduction: Cirrhosis is the end stage of any chronic liver disease. It is characterized by diffuse fibrosis with disturbed hepatic architecture. Omega-3 polyunsaturated fatty acids are common antioxidant, anti-inflammatory and anti-fibrotic agents Aim: This study was conducted to investigate the potential effects of omega-3 fatty acids on experimentally induced cirrhosis. Materials and Methods: 60 animals were divided into three groups: Group I (control): 10 animals, group II: 25 animals treated with carbon tetrachloride (CCl4), and Group III : 25 animals treated with CCl4 then with omega-3 concomitant with CCl4 for additional two weeks after induction of cirrhosis. Body weight and liver weight coefficient were measured. Liver samples were taken for histological and immunohistochemical studies. Results: Omega-3 fatty acids treatment attenuated the CCl4 induced cirrhosis. Histological studies revealed that it decreased the stage of fibrosis, and the grade of the necroinflammatory changes. Immunohistochemical studies demonstrated that apoptotic changes diminished in cirrhotic livers after treatment with omega-3 fatty acids with a significant decrease in the cleaved caspase-3 index. Furthermore, there was a significant decrease in the number of macrophages, and hepatic stellate cells activation. Conclusion: Our results suggest that omega-3 fatty acids have an anti-inflammatory and anti-fibrotic effects on CCl4 induced liver cirrhosis in mice.

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Section: Discussionsupporting

confidence: 92%

Impact of omega-3 fatty acids on evolution of carbon tetrachloride- (CCl4) induced liver cirrhosis in mice : A histological and immunohistochemical study

Abu-Dief

Mohammed

El-Haliem

et al. 2018

Egyptian Journal of Histology

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

Cited by 56 publications

References 51 publications

Impact of omega-3 fatty acids on evolution of carbon tetrachloride- (CCl4) induced liver cirrhosis in mice : A histological and immunohistochemical study

Impact of omega-3 fatty acids on evolution of carbon tetrachloride- (CCl4) induced liver cirrhosis in mice : A histological and immunohistochemical study

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

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