The function and regulation of retinoids and their receptors in hepatic stellate cells
The function and regulation of retinoids and their receptors in hepatic stellate cells
The effects of the retinoid all-trans retinoic acid (RA) on HSC proliferation and expression of HSC activation markers are investigated in vitro. Despite effectively inhibiting HSC proliferation, all-trans RA had no effects on expression of the activation markers gelatinase A, pro-collagen I, tissue inhibitor of matrix metalloproteinase-1, and -2, β1-integrin and α-smooth muscle actin (α-SMA). However, other retinoids produced by HSC may modulate genes that regulate their fibrogenic and fibrolytic properties. Therefore, reverse-phase high performance liquid chromatography was used to examine retinoids produced by HSC during progressive activation. It was demonstrated that, although retinyl palmitate decreased with activation, HSC generated all-trans RA and other retinoic acid derivatives, including 13-cis RA. Retinoids mediate their responses via nuclear retinoid receptors. However, little is known about expression of these receptors in HSC. As different retinoid receptors control different functions, the phenotypic response of HSC to retinoids may change during transformation due to different or altered levels of expression of these receptors. The expression of one of these receptors, retinoic acid receptor beta (RARβ), was therefore examined during the transformation of HSC from a quiescent to an activated phenotype. Whilst RARβ mRNA was consistently detected by northern hybridisation in freshly isolated HSC, expression dropped rapidly during HSC activation such that the mRNA became undetectable over 2-12 days of culture activation. In contrast, western blotting data showed that synthesis of RARβ protein actually increased during this time.
The potential role of RARβ in regulating growth and differentiation of HSC was examined using a RARβ selective antagonist. This antagonist was found to decrease HSC proliferation and expression of α-SMA. This suggests RARβ may be one of the major factors responsible for the progression of HSC activation and a potential, novel HSC directed therapeutic target for liver fibrosis.
University of Southampton
Jones, Emma Helen
9d6bc2ca-b02c-4472-8951-5bac9fc0aac9
2000
Jones, Emma Helen
9d6bc2ca-b02c-4472-8951-5bac9fc0aac9
Jones, Emma Helen
(2000)
The function and regulation of retinoids and their receptors in hepatic stellate cells.
University of Southampton, Doctoral Thesis.
Record type:
Thesis
(Doctoral)
Abstract
The effects of the retinoid all-trans retinoic acid (RA) on HSC proliferation and expression of HSC activation markers are investigated in vitro. Despite effectively inhibiting HSC proliferation, all-trans RA had no effects on expression of the activation markers gelatinase A, pro-collagen I, tissue inhibitor of matrix metalloproteinase-1, and -2, β1-integrin and α-smooth muscle actin (α-SMA). However, other retinoids produced by HSC may modulate genes that regulate their fibrogenic and fibrolytic properties. Therefore, reverse-phase high performance liquid chromatography was used to examine retinoids produced by HSC during progressive activation. It was demonstrated that, although retinyl palmitate decreased with activation, HSC generated all-trans RA and other retinoic acid derivatives, including 13-cis RA. Retinoids mediate their responses via nuclear retinoid receptors. However, little is known about expression of these receptors in HSC. As different retinoid receptors control different functions, the phenotypic response of HSC to retinoids may change during transformation due to different or altered levels of expression of these receptors. The expression of one of these receptors, retinoic acid receptor beta (RARβ), was therefore examined during the transformation of HSC from a quiescent to an activated phenotype. Whilst RARβ mRNA was consistently detected by northern hybridisation in freshly isolated HSC, expression dropped rapidly during HSC activation such that the mRNA became undetectable over 2-12 days of culture activation. In contrast, western blotting data showed that synthesis of RARβ protein actually increased during this time.
The potential role of RARβ in regulating growth and differentiation of HSC was examined using a RARβ selective antagonist. This antagonist was found to decrease HSC proliferation and expression of α-SMA. This suggests RARβ may be one of the major factors responsible for the progression of HSC activation and a potential, novel HSC directed therapeutic target for liver fibrosis.
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Published date: 2000
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Local EPrints ID: 466987
URI: http://eprints.soton.ac.uk/id/eprint/466987
PURE UUID: 560e0099-b8a1-410a-8a22-19fb875806a2
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Date deposited: 05 Jul 2022 08:06
Last modified: 16 Mar 2024 20:54
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Author:
Emma Helen Jones
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