BH3-only protein bid participates in the Bcl-2 network in healthy liver cells

Hayato Hikita, Tetsuo Takehara, Takahiro Kodama, Satoshi Shimizu, Atsushi Hosui, Takuya Miyagi, Tomohide Tatsumi, Hisashi Ishida, Kazuyoshi Ohkawa, Wei Li, Tatsuya Kanto, Naoki Hiramatsu, Lothar Hennighausen, Xiao-Ming Yin, Norio Hayashi

Research output: Contribution to journalArticle

16 Citations (Scopus)

Abstract

Bcl-2 homology domain 3 (BH3)-only protein Bid is posttranslationally cleaved by caspase-8 into its truncated form (tBid) and couples with stress signals to the mitochondrial cell death pathway. However, the physiological relevance of Bid is not clearly understood. Hepatocyte-specific knockout (KO) of Bcl-xL leads to naturally-occurring apoptosis despite co-expression of Mcl-1, which shares a similar anti-apoptotic function. We generated Bcl-xL KO, Bcl-xL/Bid double KO, Bcl-xL/Bak double KO, Bcl-xL/Bax double KO, and Bcl-xL/Bak/Bax triple KO mice and found that hepatocyte apoptosis caused by Bcl-xL deficiency was completely dependent on Bak and Bax, and surprisingly on Bid. This indicated that, in the absence of Bid, Bcl-xL is not required for the integrity of differentiated hepatocytes, suggesting a complicated interaction between core Bcl-2 family proteins and BH3-only proteins even in a physiological setting. Indeed, a small but significant level of tBid was present in wild-type liver under physiological conditions. tBid was capable of binding to Bcl-xL and displacing Bak and Bax from Bcl-xL, leading to release of cytochrome c from wildtype mitochondria. Bcl-xL-deficient mitochondria were more susceptible to tBid-induced cytochrome c release. Finally, administration of ABT-737, a pharmacological inhibitor of Bcl-2/BclxL, caused Bak/Bax-dependent liver injury, but this was clearly ameliorated with a Bid KO background. Conclusion: Bid, originally considered to be a sensor for apoptotic stimuli, is constitutively active in healthy liver cells and is involved in the Bak/Bax-dependent mitochondrial cell death pathway. Healthy liver cells are addicted to a single Bcl-2-like molecule because of BH3 stresses, and therefore special caution may be required for the use of the Bcl-2 inhibitor for cancer therapy.

Original languageEnglish (US)
Pages (from-to)1972-1980
Number of pages9
JournalHepatology
Volume50
Issue number6
DOIs
StatePublished - 2009
Externally publishedYes

Fingerprint

BH3 Interacting Domain Death Agonist Protein
Hepatocytes
Liver
Cytochromes c
Mitochondria
Cell Death
Apoptosis
Caspase 8
Knockout Mice
Proteins
Pharmacology
Wounds and Injuries
Neoplasms

ASJC Scopus subject areas

  • Hepatology

Cite this

Hikita, H., Takehara, T., Kodama, T., Shimizu, S., Hosui, A., Miyagi, T., ... Hayashi, N. (2009). BH3-only protein bid participates in the Bcl-2 network in healthy liver cells. Hepatology, 50(6), 1972-1980. https://doi.org/10.1002/hep.23207

BH3-only protein bid participates in the Bcl-2 network in healthy liver cells. / Hikita, Hayato; Takehara, Tetsuo; Kodama, Takahiro; Shimizu, Satoshi; Hosui, Atsushi; Miyagi, Takuya; Tatsumi, Tomohide; Ishida, Hisashi; Ohkawa, Kazuyoshi; Li, Wei; Kanto, Tatsuya; Hiramatsu, Naoki; Hennighausen, Lothar; Yin, Xiao-Ming; Hayashi, Norio.

In: Hepatology, Vol. 50, No. 6, 2009, p. 1972-1980.

Research output: Contribution to journalArticle

Hikita, H, Takehara, T, Kodama, T, Shimizu, S, Hosui, A, Miyagi, T, Tatsumi, T, Ishida, H, Ohkawa, K, Li, W, Kanto, T, Hiramatsu, N, Hennighausen, L, Yin, X-M & Hayashi, N 2009, 'BH3-only protein bid participates in the Bcl-2 network in healthy liver cells', Hepatology, vol. 50, no. 6, pp. 1972-1980. https://doi.org/10.1002/hep.23207
Hikita H, Takehara T, Kodama T, Shimizu S, Hosui A, Miyagi T et al. BH3-only protein bid participates in the Bcl-2 network in healthy liver cells. Hepatology. 2009;50(6):1972-1980. https://doi.org/10.1002/hep.23207
Hikita, Hayato ; Takehara, Tetsuo ; Kodama, Takahiro ; Shimizu, Satoshi ; Hosui, Atsushi ; Miyagi, Takuya ; Tatsumi, Tomohide ; Ishida, Hisashi ; Ohkawa, Kazuyoshi ; Li, Wei ; Kanto, Tatsuya ; Hiramatsu, Naoki ; Hennighausen, Lothar ; Yin, Xiao-Ming ; Hayashi, Norio. / BH3-only protein bid participates in the Bcl-2 network in healthy liver cells. In: Hepatology. 2009 ; Vol. 50, No. 6. pp. 1972-1980.
@article{da3044339ce647478a8c64d90ada468c,
title = "BH3-only protein bid participates in the Bcl-2 network in healthy liver cells",
abstract = "Bcl-2 homology domain 3 (BH3)-only protein Bid is posttranslationally cleaved by caspase-8 into its truncated form (tBid) and couples with stress signals to the mitochondrial cell death pathway. However, the physiological relevance of Bid is not clearly understood. Hepatocyte-specific knockout (KO) of Bcl-xL leads to naturally-occurring apoptosis despite co-expression of Mcl-1, which shares a similar anti-apoptotic function. We generated Bcl-xL KO, Bcl-xL/Bid double KO, Bcl-xL/Bak double KO, Bcl-xL/Bax double KO, and Bcl-xL/Bak/Bax triple KO mice and found that hepatocyte apoptosis caused by Bcl-xL deficiency was completely dependent on Bak and Bax, and surprisingly on Bid. This indicated that, in the absence of Bid, Bcl-xL is not required for the integrity of differentiated hepatocytes, suggesting a complicated interaction between core Bcl-2 family proteins and BH3-only proteins even in a physiological setting. Indeed, a small but significant level of tBid was present in wild-type liver under physiological conditions. tBid was capable of binding to Bcl-xL and displacing Bak and Bax from Bcl-xL, leading to release of cytochrome c from wildtype mitochondria. Bcl-xL-deficient mitochondria were more susceptible to tBid-induced cytochrome c release. Finally, administration of ABT-737, a pharmacological inhibitor of Bcl-2/BclxL, caused Bak/Bax-dependent liver injury, but this was clearly ameliorated with a Bid KO background. Conclusion: Bid, originally considered to be a sensor for apoptotic stimuli, is constitutively active in healthy liver cells and is involved in the Bak/Bax-dependent mitochondrial cell death pathway. Healthy liver cells are addicted to a single Bcl-2-like molecule because of BH3 stresses, and therefore special caution may be required for the use of the Bcl-2 inhibitor for cancer therapy.",
author = "Hayato Hikita and Tetsuo Takehara and Takahiro Kodama and Satoshi Shimizu and Atsushi Hosui and Takuya Miyagi and Tomohide Tatsumi and Hisashi Ishida and Kazuyoshi Ohkawa and Wei Li and Tatsuya Kanto and Naoki Hiramatsu and Lothar Hennighausen and Xiao-Ming Yin and Norio Hayashi",
year = "2009",
doi = "10.1002/hep.23207",
language = "English (US)",
volume = "50",
pages = "1972--1980",
journal = "Hepatology",
issn = "0270-9139",
publisher = "John Wiley and Sons Ltd",
number = "6",

}

TY - JOUR

T1 - BH3-only protein bid participates in the Bcl-2 network in healthy liver cells

AU - Hikita, Hayato

AU - Takehara, Tetsuo

AU - Kodama, Takahiro

AU - Shimizu, Satoshi

AU - Hosui, Atsushi

AU - Miyagi, Takuya

AU - Tatsumi, Tomohide

AU - Ishida, Hisashi

AU - Ohkawa, Kazuyoshi

AU - Li, Wei

AU - Kanto, Tatsuya

AU - Hiramatsu, Naoki

AU - Hennighausen, Lothar

AU - Yin, Xiao-Ming

AU - Hayashi, Norio

PY - 2009

Y1 - 2009

N2 - Bcl-2 homology domain 3 (BH3)-only protein Bid is posttranslationally cleaved by caspase-8 into its truncated form (tBid) and couples with stress signals to the mitochondrial cell death pathway. However, the physiological relevance of Bid is not clearly understood. Hepatocyte-specific knockout (KO) of Bcl-xL leads to naturally-occurring apoptosis despite co-expression of Mcl-1, which shares a similar anti-apoptotic function. We generated Bcl-xL KO, Bcl-xL/Bid double KO, Bcl-xL/Bak double KO, Bcl-xL/Bax double KO, and Bcl-xL/Bak/Bax triple KO mice and found that hepatocyte apoptosis caused by Bcl-xL deficiency was completely dependent on Bak and Bax, and surprisingly on Bid. This indicated that, in the absence of Bid, Bcl-xL is not required for the integrity of differentiated hepatocytes, suggesting a complicated interaction between core Bcl-2 family proteins and BH3-only proteins even in a physiological setting. Indeed, a small but significant level of tBid was present in wild-type liver under physiological conditions. tBid was capable of binding to Bcl-xL and displacing Bak and Bax from Bcl-xL, leading to release of cytochrome c from wildtype mitochondria. Bcl-xL-deficient mitochondria were more susceptible to tBid-induced cytochrome c release. Finally, administration of ABT-737, a pharmacological inhibitor of Bcl-2/BclxL, caused Bak/Bax-dependent liver injury, but this was clearly ameliorated with a Bid KO background. Conclusion: Bid, originally considered to be a sensor for apoptotic stimuli, is constitutively active in healthy liver cells and is involved in the Bak/Bax-dependent mitochondrial cell death pathway. Healthy liver cells are addicted to a single Bcl-2-like molecule because of BH3 stresses, and therefore special caution may be required for the use of the Bcl-2 inhibitor for cancer therapy.

AB - Bcl-2 homology domain 3 (BH3)-only protein Bid is posttranslationally cleaved by caspase-8 into its truncated form (tBid) and couples with stress signals to the mitochondrial cell death pathway. However, the physiological relevance of Bid is not clearly understood. Hepatocyte-specific knockout (KO) of Bcl-xL leads to naturally-occurring apoptosis despite co-expression of Mcl-1, which shares a similar anti-apoptotic function. We generated Bcl-xL KO, Bcl-xL/Bid double KO, Bcl-xL/Bak double KO, Bcl-xL/Bax double KO, and Bcl-xL/Bak/Bax triple KO mice and found that hepatocyte apoptosis caused by Bcl-xL deficiency was completely dependent on Bak and Bax, and surprisingly on Bid. This indicated that, in the absence of Bid, Bcl-xL is not required for the integrity of differentiated hepatocytes, suggesting a complicated interaction between core Bcl-2 family proteins and BH3-only proteins even in a physiological setting. Indeed, a small but significant level of tBid was present in wild-type liver under physiological conditions. tBid was capable of binding to Bcl-xL and displacing Bak and Bax from Bcl-xL, leading to release of cytochrome c from wildtype mitochondria. Bcl-xL-deficient mitochondria were more susceptible to tBid-induced cytochrome c release. Finally, administration of ABT-737, a pharmacological inhibitor of Bcl-2/BclxL, caused Bak/Bax-dependent liver injury, but this was clearly ameliorated with a Bid KO background. Conclusion: Bid, originally considered to be a sensor for apoptotic stimuli, is constitutively active in healthy liver cells and is involved in the Bak/Bax-dependent mitochondrial cell death pathway. Healthy liver cells are addicted to a single Bcl-2-like molecule because of BH3 stresses, and therefore special caution may be required for the use of the Bcl-2 inhibitor for cancer therapy.

UR - http://www.scopus.com/inward/record.url?scp=73149094542&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=73149094542&partnerID=8YFLogxK

U2 - 10.1002/hep.23207

DO - 10.1002/hep.23207

M3 - Article

C2 - 19839062

AN - SCOPUS:73149094542

VL - 50

SP - 1972

EP - 1980

JO - Hepatology

JF - Hepatology

SN - 0270-9139

IS - 6

ER -