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Inhibition of endothelin-1-mediated contraction of hepatic stellate cells by FXR ligand

Li, J and Kuruba, R and Wilson, A and Gao, X and Zhang, Y and Li, S (2010) Inhibition of endothelin-1-mediated contraction of hepatic stellate cells by FXR ligand. PLoS ONE, 5 (11).

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Activation of hepatic stellate cells (HSCs) plays an important role in the development of cirrhosis through the increased production of collagen and the enhanced contractile response to vasoactive mediators such as endothelin-1 (ET-1). The farnesoid X receptor (FXR) is a member of the nuclear receptor superfamily that is highly expressed in liver, kidneys, adrenals, and intestine. FXR is also expressed in HSCs and activation of FXR in HSCs is associated with significant decreases in collagen production. However, little is known about the roles of FXR in the regulation of contraction of HSCs. We report in this study that treatment of quiescent HSCs with GW4064, a synthetic FXR agonist, significantly inhibited the HSC transdifferentiation, which was associated with an inhibition of the upregulation of ET-1 expression. These GW4064-treated cells also showed reduced contractile response to ET-1 in comparison to HSCs without GW4064 treatment. We have further shown that GW4064 treatment inhibited the ET-1-mediated contraction in fully activated HSCs. To elucidate the potential mechanism we showed that GW4064 inhibited ET-1-mediated activation of Rho/ROCK pathway in activated HSCs. Our studies unveiled a new mechanism that might contribute to the anti-cirrhotic effects of FXR ligands. © 2010 Li et al.


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Item Type: Article
Status: Published
CreatorsEmailPitt UsernameORCID
Li, Jjil35@pitt.eduJIL35
Kuruba, R
Wilson, Aaswilson@pitt.eduASWILSON
Gao, X
Zhang, Y
Li, Ssol4@pitt.eduSOL4
ContributionContributors NameEmailPitt UsernameORCID
Date: 9 December 2010
Date Type: Publication
Journal or Publication Title: PLoS ONE
Volume: 5
Number: 11
DOI or Unique Handle: 10.1371/journal.pone.0013955
Refereed: Yes
MeSH Headings: Animals; Blotting, Western; Cell Shape--drug effects; Cell Transdifferentiation--drug effects; Cells, Cultured; Endothelin-1--genetics; Endothelin-1--metabolism; Endothelin-1--pharmacology; Gene Expression Regulation--drug effects; Hepatic Stellate Cells--cytology; Hepatic Stellate Cells--drug effects; Hepatic Stellate Cells--metabolism; Isoxazoles--pharmacology; Male; Microfilament Proteins--metabolism; Phosphorylation--drug effects; Rats; Rats, Sprague-Dawley; Receptors, Cytoplasmic and Nuclear--agonists; Receptors, Cytoplasmic and Nuclear--genetics; Receptors, Cytoplasmic and Nuclear--metabolism; Reverse Transcriptase Polymerase Chain Reaction; Signal Transduction--drug effects; rho-Associated Kinases--metabolism
Other ID: NLM PMC2978707
PubMed Central ID: PMC2978707
PubMed ID: 21085652
Date Deposited: 14 Aug 2012 21:19
Last Modified: 02 Feb 2019 16:58


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