title: Modulation of Bcl-x Alternative Splicing Induces Apoptosis of Human Hepatic Stellate Cells.
abstract: 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-xL and proapoptotic Bcl-xS. 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-xL was dramatically higher than Bcl-2 in activated human HSCs. The relative expression of Bcl-xL over Bcl-xS 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.
authors: Division of Molecular Pharmaceutics, UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599, USA.
authors: Lin
authors: L
authors: Wu
authors: Division of Molecular Pharmaceutics, UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599, USA.
authors: Chengqiong
authors: C
authors: Mao
authors: Division of Molecular Pharmaceutics, UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599, USA.
authors: Xin
authors: 0000-0001-8368-250X
authors: X
authors: Ming
mesh_terms: D017398:Alternative Splicing / Q000235:genetics*; D017209:Apoptosis / Q000235:genetics*; D002478:Cells, Cultured; D005786:Gene Expression Regulation / Q000235:genetics*; D055166:Hepatic Stellate Cells / Q000502:physiology*; D006801:Humans; D051020:bcl-X Protein / Q000235:genetics*
chemical_list: D051020:bcl-X Protein