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).
Abstract
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
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Status: |
Published |
Creators/Authors: |
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Contributors: |
Contribution | Contributors Name | Email | Pitt Username | ORCID  |
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Editor | Beier, Frank | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED |
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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 |
URI: |
http://d-scholarship.pitt.edu/id/eprint/13569 |
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