Hepatocyte-specific disruption of Bcl-xL leads to continuous hepatocyte apoptosis and liver fibrotic responses

T Takehara, T Tatsumi, T Suzuki, EB Rucker III… - Gastroenterology, 2004 - Elsevier
T Takehara, T Tatsumi, T Suzuki, EB Rucker III, L Hennighausen, M Jinushi, T Miyagi…
Gastroenterology, 2004Elsevier
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-xL, 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-xL in hepatocytes using the Cre-loxP
system and to analyze the consequences of long-term apoptosis in hepatocytes. Methods …
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-xL, 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-xL in hepatocytes using the Cre-loxP 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-xL-deficient mice.
Results
On AdexCre infection, primary cultured bcl-x fl/fl hepatocytes reduced their expression of Bcl-xL and rapidly underwent apoptosis associated with mitochondrial damage. In vivo hepatocyte-specific disruption of Bcl-xL resulted in spontaneous apoptosis of hepatocytes for more than 6 months. The Bcl-xL-deficient mice showed liver fibrosis with advanced age that was preceded by an increase in hepatic transforming growth factor β production. In vitro, macrophages and hepatocytes produced transforming growth factor β on exposure to apoptotic hepatocytes.
Conclusions
The present study identified Bcl-xL as 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.
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