Mcl-1 and Bcl-xL Cooperatively Maintain Integrity of Hepatocytes in Developing and Adult Murine Liver†

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

doi:10.1002/hep.23126

Cited by 115 publications

(126 citation statements)

References 32 publications

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“…For instance, fatal polycystic kidney disease and lymphopenia caused by loss of Bcl-2 are ameliorated in a Bim knock-out background (19). Similarly, we reported previously that spontaneous hepatocyte apoptosis caused by hepatocyte-specific deficiency of Bcl-xL or Mcl-1 is alleviated by Bid deficiency (20,21). These studies indicated that Bid or Bim is apparently involved in apoptotic phenotypes induced by lack of an antiapoptotic Bcl-2 family protein.…”

supporting

confidence: 73%

“…In this case, lymphocytes and other cell lineages may possess Bcl-2 and other antiapoptotic Bcl-2 proteins such as Mcl-1 (45). Hepatocyte apoptosis observed in hepatocytespecific knock-out of Mcl-1 or Bcl-xL is ameliorated in a Bid knock-out background (20,21). In this case, hepatocytes clearly have two critical antiapoptotic Bcl-2 family proteins, Bcl-xL and Mcl-1, and Bid may switch binding partners from one to the other in the case of deficiency of either protein.…”

Section: Discussionmentioning

confidence: 99%

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BH3-only Activator Proteins Bid and Bim Are Dispensable for Bak/Bax-dependent Thrombocyte Apoptosis Induced by Bcl-xL Deficiency

Kodama

Takehara

Hikita

et al. 2011

Journal of Biological Chemistry

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A pivotal step in the mitochondrial pathway of apoptosis is activation of Bak and Bax, although the molecular mechanism remains controversial. To examine whether mitochondrial apoptosis can be induced by just a lack of antiapoptotic Bcl-2-like proteins or requires direct activators of the BH3-only proteins including Bid and Bim, we studied the molecular requisites for platelet apoptosis induced by Bcl-xL deficiency. Severe thrombocytopenia induced by thrombocyte-specific Bcl-xL knock-out was fully rescued in a Bak and Bax double knock-out background but not with single knock-out of either one. In sharp contrast, deficiency of either Bid, Bim, or both did not alleviate thrombocytopenia in Bcl-xL knock-out mice. An in vitro study revealed that ABT-737, a Bad mimetic, induced platelet apoptosis in association with a conformational change of the amino terminus, translocation from the cytosol to mitochondria, and homo-oligomerization of Bax. ABT-737-induced Bax activation and apoptosis were also observed in Bid/Bim-deficient platelets. Human platelets, upon storage, underwent spontaneous apoptosis with a gradual decline of Bcl-xL expression despite a decrease in Bid and Bim expression. Apoptosis was attenuated in Bak/Bax-deficient or Bcl-xL-overexpressing platelets but not in Bid/Bim-deficient platelets upon storage. In conclusion, platelet lifespan is regulated by a fine balance between anti-and proapoptotic multidomain Bcl-2 family proteins. Despite residing in platelets, BH3-only activator proteins Bid and Bim are dispensable for Bax activation and mitochondrial apoptosis.Platelets are unique blood cells that do not have a nucleus but contain mitochondria and have the daily job of handling hemostasis and thrombosis (1). They are produced from megakaryocytes and once released into circulation can function for about 10 days in humans and 4 -5 days in mice (2). They are then thought to be destroyed by the reticuloendothelial system. Regarding the mechanism that controls their lifespan, several studies have observed a decrease in mitochondrial membrane potential, caspase activation, and phosphatidylserine exposure in platelets, leading to the conclusion that platelets undergo apoptotic cell death (3-5). It has been demonstrated that platelets contain several apoptosis-related proteins such as Bcl-2 family proteins and a variety of caspase family proteins (3-7). Recently, Mason et al. (8) reported that knock-out of a single allele of the bcl-x gene results in mild thrombocytopenia, which is ameliorated in a Bak knock-out background. We have also reported previously that thrombocyte-specific homozygous Bcl-xL knock-out mice show marked thrombocytopenia (9). These findings established the critical role of Bcl-2 family proteins in regulating platelet apoptosis and lifespan. Platelets may be the simplest model for the study of Bcl-2 biology with physiological relevance because they neither perform de novo protein synthesis nor undergo proliferation.The proapoptotic multidomain Bcl-2 family proteins Bak and Bax serve as ef...

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supporting

confidence: 73%

Section: Discussionmentioning

confidence: 99%

BH3-only Activator Proteins Bid and Bim Are Dispensable for Bak/Bax-dependent Thrombocyte Apoptosis Induced by Bcl-xL Deficiency

Kodama

Takehara

Hikita

et al. 2011

Journal of Biological Chemistry

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“…These findings show that Bcl-xL was involved in preventing mature megakaryocytes from apoptosis but was dispensable for their growth and development in vivo. We have recently reported that Mcl-1 and Bcl-xL cooperatively maintain hepatocyte integrity, 32 which led us to generate mice with megakaryocytic lineage-specific deletion of both genes. The double knockout mice developed loss of mature megakaryocytes in the fetal liver.…”

Section: Discussionmentioning

confidence: 99%

Mcl-1 and Bcl-xL regulate Bak/Bax-dependent apoptosis of the megakaryocytic lineage at multistages

et al. 2012

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“…Both anti-apoptotic proteins Mcl-1 and Bcl-x L have a critical role for liver cell survival 49 because of their ability to maintain mitochondrial integrity. Previous studies have reported that saturated FFA induce a rapid loss of Bcl-x L and Mcl-1, which contributes to hepatocyte lipoapoptosis.…”

Section: Discussionmentioning

confidence: 99%

Degradation of Keap1 activates BH3-only proteins Bim and PUMA during hepatocyte lipoapoptosis

et al. 2014

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Non-alcoholic steatohepatitis is characterized by hepatic steatosis, elevated levels of circulating free fatty acids (FFA) and hepatocyte lipoapoptosis. This lipoapoptosis requires increased JNK phosphorylation and activation of the pro-apoptotic BH3-only proteins Bim and PUMA. Kelch-like ECH-associated protein (Keap)-1 is a BTB/Kelch protein that can regulate the expression of Bcl-2 protein and control apoptotic cell death. Yet, the role of Keap1 in hepatocyte lipotoxicity is unclear. Here we demonstrate that Keap1 protein was rapidly degraded in hepatocytes, through autophagy in a p62-dependent manner, in response to the toxic saturated FFA palmitate, but not following incubation with the non-toxic FFA oleic acid. Stable knockdown of Keap1 expression, using shRNA technology, in hepatocarcinoma cell lines induced spontaneous cell toxicity that was associated with JNK1-dependent upregulation of Bim and PUMA protein levels. Also, Keap1 knockdown further sensitized hepatocytes to lipoapoptosis by palmitate. Likewise, primary hepatocytes isolated from liver-specific Keap1 À / À mice displayed higher Bim and PUMA protein levels and demonstrated increased sensitivity to palmitate-induced apoptosis than wild-type mouse hepatocytes. Finally, stable knockdown of Bim or PUMA expression prevented cell toxicity induced by loss of Keap1. These results implicate p62-dependent autophagic degradation of Keap1 by palmitate as a mechanism contributing to hepatocyte lipoapoptosis.

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Mcl-1 and Bcl-xL Cooperatively Maintain Integrity of Hepatocytes in Developing and Adult Murine Liver†

Cited by 115 publications

References 32 publications

BH3-only Activator Proteins Bid and Bim Are Dispensable for Bak/Bax-dependent Thrombocyte Apoptosis Induced by Bcl-xL Deficiency

BH3-only Activator Proteins Bid and Bim Are Dispensable for Bak/Bax-dependent Thrombocyte Apoptosis Induced by Bcl-xL Deficiency

Mcl-1 and Bcl-xL regulate Bak/Bax-dependent apoptosis of the megakaryocytic lineage at multistages

Degradation of Keap1 activates BH3-only proteins Bim and PUMA during hepatocyte lipoapoptosis

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