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

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72 Scopus citations

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 - Dec 1 2009

ASJC Scopus subject areas

  • Hepatology

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    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, 50(4), 1217-1226. https://doi.org/10.1002/hep.23126