期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 288, 期 42, 页码 30009-30018出版社
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M112.443093
关键词
Bcl-2 Family Proteins; Cell Biology; Hepatocyte; Liver Injury; Mitochondrial Apoptosis; Bcl-xl; Mcl-1
资金
- Ministry of Education, Culture, Sports, Science, and Technology of Japan
- Grants-in-Aid for Scientific Research [24590973, 23390197] Funding Source: KAKEN
Background: A fine balance between the anti- and pro-apoptotic multidomain Bcl-2 family proteins controls hepatocyte apoptosis in the healthy liver. Results: Disruption of the BH3-only proteins Bim and Bid prevents spontaneous hepatocyte apoptosis in the absence of anti-apoptotic Bcl-2 family proteins. Conclusion: Hepatocyte integrity is maintained by the well orchestrated Bcl-2 network. Significance: We demonstrated the novel involvement of BH3-only proteins in the healthy Bcl-2 network of the liver. An intrinsic pathway of apoptosis is regulated by the B-cell lymphoma-2 (Bcl-2) family proteins. We previously reported that a fine rheostatic balance between the anti- and pro-apoptotic multidomain Bcl-2 family proteins controls hepatocyte apoptosis in the healthy liver. The Bcl-2 homology domain 3 (BH3)-only proteins set this rheostatic balance toward apoptosis upon activation in the diseased liver. However, their involvement in healthy Bcl-2 rheostasis remains unknown. In the present study, we focused on two BH3-only proteins, Bim and Bid, and we clarified the Bcl-2 network that governs hepatocyte life and death in the healthy liver. We generated hepatocyte-specific Bcl-xL- or Mcl-1-knock-out mice, with or without disrupting Bim and/or Bid, and we examined hepatocyte apoptosis under physiological conditions. We also examined the effect of both Bid and Bim disruption on the hepatocyte apoptosis caused by the inhibition of Bcl-xL and Mcl-1. Spontaneous hepatocyte apoptosis in Bcl-xL- or Mcl-1-knock-out mice was significantly ameliorated by Bim deletion. The disruption of both Bim and Bid completely prevented hepatocyte apoptosis in Bcl-xL-knock-out mice and weakened massive hepatocyte apoptosis via the additional in vivo knockdown of mcl-1 in these mice. Finally, the hepatocyte apoptosis caused by ABT-737, which is a Bcl-xL/Bcl-2/Bcl-w inhibitor, was completely prevented in Bim/Bid double knock-out mice. The BH3-only proteins Bim and Bid are functionally active but are restrained by the anti-apoptotic Bcl-2 family proteins under physiological conditions. Hepatocyte integrity is maintained by the dynamic and well orchestrated Bcl-2 network in the healthy liver.
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