Essential Roles of RNA-binding Protein HuR in Activation of Hepatic Stellate Cells Induced by Transforming Growth Factor-β1

Ge, Jingjing; Chang, Na; Zhang, Zhao; Tian, Lei; Duan, Xianghui; Yang, Lin; Li, Liying

doi:10.1038/srep22141

Cited by 27 publications

(23 citation statements)

References 53 publications

(85 reference statements)

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“…TGF-β1 is a major profibrogenic cytokine and plays a vital role in the activation of HSCs. Particularly, TGF-β1 induces phenotypic transdifferentiation of HSCs and synthesis of ECM29. PDGF-B is the most potent stimulus for HSCs proliferation and migration and contributes to the perpetuation of liver fibrosis30.…”

Section: Discussionmentioning

confidence: 99%

Reduction of hepatic fibrosis by overexpression of von Hippel–Lindau protein in experimental models of chronic liver disease

Wang

et al. 2017

Sci Rep

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Hypoxia-inducible factor (HIF)-1α and HIF-2α play an important role in liver fibrosis. von Hippel-Lindau protein (VHL), a key mediator of HIF-α, regulates fibrosis in an organ-and cell-specific way. In this study, human liver samples were collected from hepatitis C-, alcoholic-, and cholestatic-associated fibrotic and healthy individuals. Two mouse models of liver fibrosis were established: bile duct ligation and carbon tetrachloride injection. We constructed adenovirus vectors to overexpress VHL, normoxiaactive HIF-α, and lentiviral vectors to silence HIF-α. The results showed that liver sections from fibrosis patients had a lower level of VHL and higher levels of HIF-1α and HIF-2α compared with healthy sections, a finding which was confirmed in mice. Overexpression of VHL attenuated liver fibrosis, downregulated fibrogenic genes, and inhibited liver inflammation, apoptosis, and angiogenesis. Overexpression of VHL was more successful at inhibiting fibrosis compared with silencing HIF-1α plus HIF-2α. Normoxia-active HIF-1α or HIF-2α prevented the inhibitory effect of VHL on liver fibrosis, indicating that attenuating fibrosis via VHL is HIF-1α-and HIF-2α-dependent to some extent. In addition, overexpression of VHL inhibited mouse hepatic stellate cells activation and proliferation and promoted apoptosis. Taken together, VHL may be considered a new target to inhibit liver fibrosis.

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Section: Discussionmentioning

confidence: 99%

Reduction of hepatic fibrosis by overexpression of von Hippel–Lindau protein in experimental models of chronic liver disease

Wang

et al. 2017

Sci Rep

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“…The interaction between LARP6 and STRAP is regulated by the mammalian target of rapamycin mTORC1, which phosphorylates serine residues 348 and 409 of LARP6, facilitating its release from endoplasmic reticulum [140]. The role of another RNA binding protein, HuR (Hu-antigen R or ELAV-like protein 1), has been reported in liver fibrosis [141,142]. HuR is a member of the embryonic lethal abnormal vision (ELAV)-like/Hu-protein family of RNA binding proteins, which regulate stability, splicing and translation of RNAs [143].…”

Section: Stabilization Of Collagen Mrnasmentioning

confidence: 99%

“…Its expression is increased during the activation of HSCs, and silencing of HuR reduces liver fibrosis after bile duct ligation in mice [142]. HuRmediated HSC activation requires binding to sphingosine kinase 1 (SphK1) mRNA, a known regulator of TGF-β1-dependent expression of COL1A1 or α -SMA [141]. More recently, the long non-coding RNA TSIX has been identified as a new regulator of collagen mRNA stability in scleroderma fibroblasts [144].…”

Section: Stabilization Of Collagen Mrnasmentioning

confidence: 99%

Molecular and tissue alterations of collagens in fibrosis

2018

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The collagen network is altered in fibrotic diseases associated with extracellular matrix (ECM) biosynthesis and remodeling. This mini-review focuses on the quantitative and qualitative modifications of collagens occurring at the molecular and tissue levels in fibrosis. They result from changes in collagen expression, biosynthesis, enzymatic cross-linking and degradation by several protease families. These molecular modifications, which are mostly regulated by TGF-β, are associated with altered collagen organization at the tissue level, leading to a fibrotic signature that can be analyzed by Second Harmonic Generation (SHG) microscopy.

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“…The excessive accumulation of extracellular matrix is the main characteristic and is primarily generated by myofibroblasts. Hepatic stellate cells (HSCs) are the major source of extracellular matrix, which can be activated by many inflammatory cytokines in liver fibrosis (2,3). Some investigators have proved that microRNAs (miRNAs) play a vital role in this pathologic process of liver fibrosis, including miR-19b, miR-29, miR-146a, miR-150, miR-194, miR-122, miR-199, and miR-200 (4-9).…”

mentioning

confidence: 99%

rSjP40 protein promotes PPARγ expression in LX‐2 cells through microRNA‐27b

et al. 2018

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miR-27b is reported to participate in the proliferation and differentiation of hepatic stellate cells (HSCs) and to regulate fat metabolism of rat HSCs by targeting retinoid X receptor α. Our previous study also indicated that the recombinant P40 protein from Schistosoma japonicum (rSjP40) inhibited the activation of HSCs. In this study, we observed the expression of miR-27b in rSjP40-treated LX-2 cells and explored its potential mechanisms. Quantitative real-time PCR showed that rSjP40 inhibits the expression of miR-27b in LX-2 cells. Further results obtained by Western blot and dual-luciferase reporter assay confirmed that miR-27b regulates peroxisome proliferator-activated receptor γ (PPARγ) expression in rSjP40-treated LX-2 cells by targeting the 3'-UTR of PPARγ. 5-AZA-2'-deoxycytidine (5-AZA-dC), which inhibits methylation of HSCs, partially reversed rSjP40-induced down-regulation expression of miR-27b in LX-2 cells. 5-AZA-dC also partially reversed rSjP40-induced up-regulation expression of PPARγ in LX-2 cells. The increased expression of PPARγ in rSjP40-treated LX-2 cells may be partially due to miR-27b methylation. Therefore, our study provides further insight into the mechanism by which rSjP40 inhibits HSC activation and provides a basis for future study of the blocking effect of rSjP40 in liver fibrosis.-Zhu, D., Lyu, L., Shen, P., Wang, J., Chen, J., Sun, X., Chen, L., Zhang, L., Zhou, Q., Duan, Y. rSjP40 protein promotes PPARγ expression in LX-2 cells through microRNA-27b.

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Essential Roles of RNA-binding Protein HuR in Activation of Hepatic Stellate Cells Induced by Transforming Growth Factor-β1

Cited by 27 publications

References 53 publications

Reduction of hepatic fibrosis by overexpression of von Hippel–Lindau protein in experimental models of chronic liver disease

Reduction of hepatic fibrosis by overexpression of von Hippel–Lindau protein in experimental models of chronic liver disease

Molecular and tissue alterations of collagens in fibrosis

rSjP40 protein promotes PPARγ expression in LX‐2 cells through microRNA‐27b

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