Hepatocyte-specific disruption of Bcl-xL leads to continuous hepatocyte apoptosis and liver fibrotic responses
Tetsuo Takehara, Tomohide Tatsumi, Takahiro Suzuki, Edmund B. Rucker, Lothar Hennighausen, Masahisa Jinushi, Takuya Miyagi, Yoshiyuki Kanazawa, Norio Hayashi
Background & Aims: Recent research has suggested that apoptosis could be involved in the development of fibrosis, although it is generally considered to be a mechanism of cell removal without consequences to the tissue. Bcl-x L, an antiapoptotic member of the Bcl-2 family, is expressed in hepatocytes and up-modulated during various pathologic conditions. The aim of this study was to explore the function of Bcl-x Lin hepatocytes using the Cre- lox P system and to analyze the consequences of long-term apoptosis in hepatocytes. Methods: Hepatocytes isolated from mice homozygous for a floxed bcl-x allele ( bcl-x fl/fl ) were infected with recombinant adenovirus expressing the Cre recombinase gene (AdexCre). Bcl-x fl/fl mice were crossed with Alb-Cre transgenic mice, which express Cre under regulation of the albumin gene promoter to generate hepatocyte-specific Bcl-x L-deficient mice. Results: On AdexCre infection, primary cultured bcl-x fl/fl hepatocytes reduced their expression of Bcl-x Land rapidly underwent apoptosis associated with mitochondrial damage. In vivo hepatocyte-specific disruption of Bcl-x Lresulted in spontaneous apoptosis of hepatocytes for more than 6 months. The Bcl-x L-deficient mice showed liver fibrosis with advanced age that was preceded by an increase in hepatic transforming growth factor ? production. In vitro, macrophages and hepatocytes produced transforming growth factor ? on exposure to apoptotic hepatocytes. Conclusions: The present study identified Bcl-x Las a critical apoptosis antagonist in hepatocytes. Furthermore, it offers proof that persistent apoptosis of parenchymal cells is sufficient to induce fibrotic responses and suggests a mechanistic link between apoptosis and fibrosis.
© 2004 by the American Gastroenterological Association
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