Mcl-1 and Bcl-xL cooperatively maintain integrity of hepatocytes in developing and adult murine liver.
Mcl-1 and Bcl-xL cooperatively maintain integrity of hepatocytes in developing and adult murine liver.
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DOI：
10.1002/hep.23126
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发表时间：
2009-10
期刊：
影响因子：
13.5
通讯作者：
Hayashi, Norio
中科院分区：
文献类型：
--
作者：
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
抗凋亡的Bcl-2家族成员，包括Bcl-2、Bcl-xL、Mcl-1、Bcl-w和bcl -1，抑制线粒体凋亡途径。Bcl-xL和Mcl-1在肝脏中组成性表达。虽然先前的研究证实Bcl-xL是分化肝细胞的关键凋亡拮抗剂，但Mcl-1在肝脏中的意义，特别是与Bcl-xL联合的意义尚不清楚。为了研究这个问题，我们通过杂交mcl-1flox/flox小鼠和AlbCre小鼠产生肝细胞特异性Mcl-1缺陷小鼠，并进一步将它们与bcl-xflox/flox小鼠杂交，得到Mcl-1/Bcl-xL缺陷小鼠。mcl-1flox/flox AlbCre小鼠出生后肝细胞自发凋亡，血清丙氨酸氨基转移酶（ALT）和caspase-3/7活性升高，肝脏末端脱氧核苷酸转移酶介导的2 ' -脱氧尿苷5 ' -三磷酸镍端标记（TUNEL）阳性细胞数量增加；这些表型与先前在肝细胞特异性Bcl-xL缺陷小鼠中发现的表型非常接近。虽然mcl-1flox/+ AlbCre小鼠未出现凋亡，但其对fas介导的肝损伤的易感性显著增加。进一步将Mcl-1小鼠与Bcl-xL小鼠杂交发现，bcl-xflox/+ mcl-1flox/+ AlbCre小鼠也表现出与Bcl-xL -缺陷或Mcl-1 -缺陷小鼠相似的自发性肝细胞凋亡。相比而言，bcl-xflox/flox mcl-1flox/+ AlbCre、bcl-xflox/+ mcl-1flox/flox AlbCre、bcl-xflox/flox mcl-1flox/flox AlbCre小鼠在胚胎发生第18.5天肝细胞数量减少，肝脏体积减小，出生后1天内迅速死亡，发生肝功能衰竭，血氨和胆红素水平升高。结论：Mcl-1在阻止成人肝脏细胞凋亡中起关键作用，在缺乏Bcl-xL的情况下，对正常肝脏发育至关重要。Mcl-1和Bcl-xL是肝脏中表达的两个主要抗凋亡Bcl-2家族蛋白，在肝脏发育和成人肝脏稳态过程中以基因剂量依赖的方式协同控制肝脏完整性。
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-1flox/+ 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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影响因子：
3.8
作者：
Schulze-Bergkamen H;Fleischer B;Schuchmann M;Weber A;Weinmann A;Krammer PH;Galle PR
通讯作者：
Galle PR
影响因子：
13.5
作者：
Llovet, Josep M.;Bruix, Jordi
通讯作者：
Bruix, Jordi
影响因子：
11.2
作者：
Liu, Li;Cao, Yichen;Carter, Christopher
通讯作者：
Carter, Christopher
影响因子：
13.5
作者：
Takehara, T;Liu, XL;Takahashi, H
通讯作者：
Takahashi, H
影响因子：
64.5
作者：
VEIS, DJ;SORENSON, CM;KORSMEYER, SJ
通讯作者：
KORSMEYER, SJ