Mcl-1 and Bcl-xL cooperatively maintain integrity of hepatocytes in developing and adult murine liver

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

Research output: Contribution to journalArticle

58 Citations (Scopus)

Abstract

Anti-apoptotic members of the Bcl-2 family, including Bcl-2, Bcl-xL, Mcl-1, Bcl-w and Bfl-1, inhibit the mitochondrial pathway of apoptosis. Bcl-xL and Mcl-1 are constitutively expressed in the liver. Although previous research established Bcl-xL as a critical apoptosis antagonist in differentiated hepatocytes, the significance of Mcl-1 in the liver, especially in conjunction with Bcl-xL, has not been clear. To examine this question, we generated hepatocyte-specific Mcl-1-deficient mice by crossing mcl-1flox/flox mice and AlbCre mice and further crossed them with bcl-xflox/flox mice, giving Mcl-1/Bcl-xL-deficient mice. The mcl-1flox/flox AlbCre mice showed spontaneous apoptosis of hepatocytes after birth, as evidenced by elevated levels of serum alanine aminotransferase (ALT) and caspase-3/7 activity and an increased number of terminal deoxynucleotidyl transferase-mediated 2′-deoxyuridine 5′-triphosphate nick-end labeling (TUNEL)-positive cells in the liver; these phenotypes were very close to those previously found in hepatocyte-specific Bcl-xL-deficient mice. Although mcl-1flox/+ AlbCre mice did not display apoptosis, their susceptibility to Fas-mediated liver injury significantly increased. Further crossing of Mcl-1 mice with Bcl-xL mice showed that bcl-xflox/+ mcl-1flox/+ AlbCre mice also showed spontaneous hepatocyte apoptosis similar to Bcl-xL-deficient or Mcl-1-deficient mice. In contrast, bcl-xflox/flox mcl-1 flox/+ AlbCre, bcl-xflox/+ mcl-1flox/flox AlbCre, and bcl-xflox/flox mcl-1flox/flox AlbCre mice displayed a decreased number of hepatocytes and a reduced volume of the liver on day 18.5 of embryogenesis and rapidly died within 1 day after birth, developing hepatic failure evidenced by increased levels of blood ammonia and bilirubin. Conclusion: Mcl-1 is critical for blocking apoptosis in adult liver and, in the absence of Bcl-xL, is essential for normal liver development. Mcl-1 and Bcl-xL are two major anti-apoptotic Bcl-2 family proteins expressed in the liver and cooperatively control hepatic integrity during liver development and in adult liver homeostasis in a gene dose-dependent manner.

Original languageEnglish (US)
Pages (from-to)1217-1226
Number of pages10
JournalHepatology
Volume50
Issue number4
DOIs
StatePublished - 2009
Externally publishedYes

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Hepatocytes
Liver
Apoptosis
Parturition
Caspase 7
DNA Nucleotidylexotransferase
Liver Failure
In Situ Nick-End Labeling
Alanine Transaminase
Bilirubin
Ammonia
Caspase 3
Embryonic Development
Homeostasis
Phenotype

ASJC Scopus subject areas

  • Hepatology
  • Medicine(all)

Cite this

Hikita, H., Takehara, T., Shimizu, S., Kodama, T., Li, W., Miyagi, T., ... Hayashi, N. (2009). Mcl-1 and Bcl-xL cooperatively maintain integrity of hepatocytes in developing and adult murine liver. Hepatology, 50(4), 1217-1226. https://doi.org/10.1002/hep.23126

Mcl-1 and Bcl-xL cooperatively maintain integrity of hepatocytes in developing and adult murine liver. / Hikita, Hayato; Takehara, Tetsuo; Shimizu, Satoshi; Kodama, Takahiro; Li, Wei; Miyagi, Takuya; Hosui, Atsushi; Ishida, Hisashi; Ohkawa, Kazuyoshi; Kanto, Tatsuya; Hiramatsu, Naoki; Yin, Xiao-Ming; Hennighausen, Lothar; Tatsumi, Tomohide; Hayashi, Norio.

In: Hepatology, Vol. 50, No. 4, 2009, p. 1217-1226.

Research output: Contribution to journalArticle

Hikita, H, Takehara, T, Shimizu, S, Kodama, T, Li, W, Miyagi, T, Hosui, A, Ishida, H, Ohkawa, K, Kanto, T, Hiramatsu, N, Yin, X-M, Hennighausen, L, Tatsumi, T & Hayashi, N 2009, 'Mcl-1 and Bcl-xL cooperatively maintain integrity of hepatocytes in developing and adult murine liver', Hepatology, vol. 50, no. 4, pp. 1217-1226. https://doi.org/10.1002/hep.23126
Hikita, Hayato ; Takehara, Tetsuo ; Shimizu, Satoshi ; Kodama, Takahiro ; Li, Wei ; Miyagi, Takuya ; Hosui, Atsushi ; Ishida, Hisashi ; Ohkawa, Kazuyoshi ; Kanto, Tatsuya ; Hiramatsu, Naoki ; Yin, Xiao-Ming ; Hennighausen, Lothar ; Tatsumi, Tomohide ; Hayashi, Norio. / Mcl-1 and Bcl-xL cooperatively maintain integrity of hepatocytes in developing and adult murine liver. In: Hepatology. 2009 ; Vol. 50, No. 4. pp. 1217-1226.
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abstract = "Anti-apoptotic members of the Bcl-2 family, including Bcl-2, Bcl-xL, Mcl-1, Bcl-w and Bfl-1, inhibit the mitochondrial pathway of apoptosis. Bcl-xL and Mcl-1 are constitutively expressed in the liver. Although previous research established Bcl-xL as a critical apoptosis antagonist in differentiated hepatocytes, the significance of Mcl-1 in the liver, especially in conjunction with Bcl-xL, has not been clear. To examine this question, we generated hepatocyte-specific Mcl-1-deficient mice by crossing mcl-1flox/flox mice and AlbCre mice and further crossed them with bcl-xflox/flox mice, giving Mcl-1/Bcl-xL-deficient mice. The mcl-1flox/flox AlbCre mice showed spontaneous apoptosis of hepatocytes after birth, as evidenced by elevated levels of serum alanine aminotransferase (ALT) and caspase-3/7 activity and an increased number of terminal deoxynucleotidyl transferase-mediated 2′-deoxyuridine 5′-triphosphate nick-end labeling (TUNEL)-positive cells in the liver; these phenotypes were very close to those previously found in hepatocyte-specific Bcl-xL-deficient mice. Although mcl-1flox/+ AlbCre mice did not display apoptosis, their susceptibility to Fas-mediated liver injury significantly increased. Further crossing of Mcl-1 mice with Bcl-xL mice showed that bcl-xflox/+ mcl-1flox/+ AlbCre mice also showed spontaneous hepatocyte apoptosis similar to Bcl-xL-deficient or Mcl-1-deficient mice. In contrast, bcl-xflox/flox mcl-1 flox/+ AlbCre, bcl-xflox/+ mcl-1flox/flox AlbCre, and bcl-xflox/flox mcl-1flox/flox AlbCre mice displayed a decreased number of hepatocytes and a reduced volume of the liver on day 18.5 of embryogenesis and rapidly died within 1 day after birth, developing hepatic failure evidenced by increased levels of blood ammonia and bilirubin. Conclusion: Mcl-1 is critical for blocking apoptosis in adult liver and, in the absence of Bcl-xL, is essential for normal liver development. Mcl-1 and Bcl-xL are two major anti-apoptotic Bcl-2 family proteins expressed in the liver and cooperatively control hepatic integrity during liver development and in adult liver homeostasis in a gene dose-dependent manner.",
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T1 - Mcl-1 and Bcl-xL cooperatively maintain integrity of hepatocytes in developing and adult murine liver

AU - Hikita, Hayato

AU - Takehara, Tetsuo

AU - Shimizu, Satoshi

AU - Kodama, Takahiro

AU - Li, Wei

AU - Miyagi, Takuya

AU - Hosui, Atsushi

AU - Ishida, Hisashi

AU - Ohkawa, Kazuyoshi

AU - Kanto, Tatsuya

AU - Hiramatsu, Naoki

AU - Yin, Xiao-Ming

AU - Hennighausen, Lothar

AU - Tatsumi, Tomohide

AU - Hayashi, Norio

PY - 2009

Y1 - 2009

N2 - Anti-apoptotic members of the Bcl-2 family, including Bcl-2, Bcl-xL, Mcl-1, Bcl-w and Bfl-1, inhibit the mitochondrial pathway of apoptosis. Bcl-xL and Mcl-1 are constitutively expressed in the liver. Although previous research established Bcl-xL as a critical apoptosis antagonist in differentiated hepatocytes, the significance of Mcl-1 in the liver, especially in conjunction with Bcl-xL, has not been clear. To examine this question, we generated hepatocyte-specific Mcl-1-deficient mice by crossing mcl-1flox/flox mice and AlbCre mice and further crossed them with bcl-xflox/flox mice, giving Mcl-1/Bcl-xL-deficient mice. The mcl-1flox/flox AlbCre mice showed spontaneous apoptosis of hepatocytes after birth, as evidenced by elevated levels of serum alanine aminotransferase (ALT) and caspase-3/7 activity and an increased number of terminal deoxynucleotidyl transferase-mediated 2′-deoxyuridine 5′-triphosphate nick-end labeling (TUNEL)-positive cells in the liver; these phenotypes were very close to those previously found in hepatocyte-specific Bcl-xL-deficient mice. Although mcl-1flox/+ AlbCre mice did not display apoptosis, their susceptibility to Fas-mediated liver injury significantly increased. Further crossing of Mcl-1 mice with Bcl-xL mice showed that bcl-xflox/+ mcl-1flox/+ AlbCre mice also showed spontaneous hepatocyte apoptosis similar to Bcl-xL-deficient or Mcl-1-deficient mice. In contrast, bcl-xflox/flox mcl-1 flox/+ AlbCre, bcl-xflox/+ mcl-1flox/flox AlbCre, and bcl-xflox/flox mcl-1flox/flox AlbCre mice displayed a decreased number of hepatocytes and a reduced volume of the liver on day 18.5 of embryogenesis and rapidly died within 1 day after birth, developing hepatic failure evidenced by increased levels of blood ammonia and bilirubin. Conclusion: Mcl-1 is critical for blocking apoptosis in adult liver and, in the absence of Bcl-xL, is essential for normal liver development. Mcl-1 and Bcl-xL are two major anti-apoptotic Bcl-2 family proteins expressed in the liver and cooperatively control hepatic integrity during liver development and in adult liver homeostasis in a gene dose-dependent manner.

AB - Anti-apoptotic members of the Bcl-2 family, including Bcl-2, Bcl-xL, Mcl-1, Bcl-w and Bfl-1, inhibit the mitochondrial pathway of apoptosis. Bcl-xL and Mcl-1 are constitutively expressed in the liver. Although previous research established Bcl-xL as a critical apoptosis antagonist in differentiated hepatocytes, the significance of Mcl-1 in the liver, especially in conjunction with Bcl-xL, has not been clear. To examine this question, we generated hepatocyte-specific Mcl-1-deficient mice by crossing mcl-1flox/flox mice and AlbCre mice and further crossed them with bcl-xflox/flox mice, giving Mcl-1/Bcl-xL-deficient mice. The mcl-1flox/flox AlbCre mice showed spontaneous apoptosis of hepatocytes after birth, as evidenced by elevated levels of serum alanine aminotransferase (ALT) and caspase-3/7 activity and an increased number of terminal deoxynucleotidyl transferase-mediated 2′-deoxyuridine 5′-triphosphate nick-end labeling (TUNEL)-positive cells in the liver; these phenotypes were very close to those previously found in hepatocyte-specific Bcl-xL-deficient mice. Although mcl-1flox/+ AlbCre mice did not display apoptosis, their susceptibility to Fas-mediated liver injury significantly increased. Further crossing of Mcl-1 mice with Bcl-xL mice showed that bcl-xflox/+ mcl-1flox/+ AlbCre mice also showed spontaneous hepatocyte apoptosis similar to Bcl-xL-deficient or Mcl-1-deficient mice. In contrast, bcl-xflox/flox mcl-1 flox/+ AlbCre, bcl-xflox/+ mcl-1flox/flox AlbCre, and bcl-xflox/flox mcl-1flox/flox AlbCre mice displayed a decreased number of hepatocytes and a reduced volume of the liver on day 18.5 of embryogenesis and rapidly died within 1 day after birth, developing hepatic failure evidenced by increased levels of blood ammonia and bilirubin. Conclusion: Mcl-1 is critical for blocking apoptosis in adult liver and, in the absence of Bcl-xL, is essential for normal liver development. Mcl-1 and Bcl-xL are two major anti-apoptotic Bcl-2 family proteins expressed in the liver and cooperatively control hepatic integrity during liver development and in adult liver homeostasis in a gene dose-dependent manner.

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