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Modulation of Bcl-x Alternative Splicing Induces Apoptosis of Human Hepatic Stellate Cells

Liver fibrosis is a major cause of morbidity and mortality worldwide due to chronic viral hepatitis and, more recently, from fatty liver diseases. Activation and proliferation of hepatic stellate cells (HSCs) represent a key aspect of fibrogenesis and are associated with progressive reduction of HSC...

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Autores principales: Wu, Lin, Mao, Chengqiong, Ming, Xin
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Hindawi Publishing Corporation 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4992517/
https://www.ncbi.nlm.nih.gov/pubmed/27579319
http://dx.doi.org/10.1155/2016/7478650
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author Wu, Lin
Mao, Chengqiong
Ming, Xin
author_facet Wu, Lin
Mao, Chengqiong
Ming, Xin
author_sort Wu, Lin
collection PubMed
description Liver fibrosis is a major cause of morbidity and mortality worldwide due to chronic viral hepatitis and, more recently, from fatty liver diseases. Activation and proliferation of hepatic stellate cells (HSCs) represent a key aspect of fibrogenesis and are associated with progressive reduction of HSC apoptosis. Bcl-x, an antiapoptotic member of Bcl-2 gene family, plays a role in apoptosis regulation in mammalian cells. Through alternative splicing, the Bcl-x gene yields two major protein isoforms with opposing functions, antiapoptotic Bcl-x(L) and proapoptotic Bcl-x(S). This study aimed to investigate the role of Bcl-x and its alternate splicing in HSC apoptosis. The results indicated that the expression of Bcl-x(L) was dramatically higher than Bcl-2 in activated human HSCs. The relative expression of Bcl-x(L) over Bcl-x(S) increased gradually when HSCs were activated in cell culture, which was consistent with the increase in apoptosis resistance of activated HSCs. Redirection of Bcl-x splicing by an antisense oligonucleotide from the antiapoptotic isoform to the proapoptotic isoform induced death of HSCs without other apoptosis stimuli. We conclude that Bcl-x plays a role in regulation of HSC apoptosis and modulation of Bcl-x alternative splicing may become a novel molecular therapy for liver fibrosis.
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spelling pubmed-49925172016-08-30 Modulation of Bcl-x Alternative Splicing Induces Apoptosis of Human Hepatic Stellate Cells Wu, Lin Mao, Chengqiong Ming, Xin Biomed Res Int Research Article Liver fibrosis is a major cause of morbidity and mortality worldwide due to chronic viral hepatitis and, more recently, from fatty liver diseases. Activation and proliferation of hepatic stellate cells (HSCs) represent a key aspect of fibrogenesis and are associated with progressive reduction of HSC apoptosis. Bcl-x, an antiapoptotic member of Bcl-2 gene family, plays a role in apoptosis regulation in mammalian cells. Through alternative splicing, the Bcl-x gene yields two major protein isoforms with opposing functions, antiapoptotic Bcl-x(L) and proapoptotic Bcl-x(S). This study aimed to investigate the role of Bcl-x and its alternate splicing in HSC apoptosis. The results indicated that the expression of Bcl-x(L) was dramatically higher than Bcl-2 in activated human HSCs. The relative expression of Bcl-x(L) over Bcl-x(S) increased gradually when HSCs were activated in cell culture, which was consistent with the increase in apoptosis resistance of activated HSCs. Redirection of Bcl-x splicing by an antisense oligonucleotide from the antiapoptotic isoform to the proapoptotic isoform induced death of HSCs without other apoptosis stimuli. We conclude that Bcl-x plays a role in regulation of HSC apoptosis and modulation of Bcl-x alternative splicing may become a novel molecular therapy for liver fibrosis. Hindawi Publishing Corporation 2016 2016-08-07 /pmc/articles/PMC4992517/ /pubmed/27579319 http://dx.doi.org/10.1155/2016/7478650 Text en Copyright © 2016 Lin Wu et al. https://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research Article
Wu, Lin
Mao, Chengqiong
Ming, Xin
Modulation of Bcl-x Alternative Splicing Induces Apoptosis of Human Hepatic Stellate Cells
title Modulation of Bcl-x Alternative Splicing Induces Apoptosis of Human Hepatic Stellate Cells
title_full Modulation of Bcl-x Alternative Splicing Induces Apoptosis of Human Hepatic Stellate Cells
title_fullStr Modulation of Bcl-x Alternative Splicing Induces Apoptosis of Human Hepatic Stellate Cells
title_full_unstemmed Modulation of Bcl-x Alternative Splicing Induces Apoptosis of Human Hepatic Stellate Cells
title_short Modulation of Bcl-x Alternative Splicing Induces Apoptosis of Human Hepatic Stellate Cells
title_sort modulation of bcl-x alternative splicing induces apoptosis of human hepatic stellate cells
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4992517/
https://www.ncbi.nlm.nih.gov/pubmed/27579319
http://dx.doi.org/10.1155/2016/7478650
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