Impaired liver regeneration in mice lacking methionine adenosyltransferase 1A
Impaired liver regeneration in mice lacking methionine adenosyltransferase 1A
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DOI：
10.1096/fj.03-1204fje
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发表时间：
2004-03-01
期刊：
影响因子：
4.8
通讯作者：
Lu, SC
中科院分区：
文献类型：
--
作者：
Chen, LX;Zeng, Y;Lu, SC
甲硫氨酸腺苷转移酶（MAT）是一种必需的酶，因为它催化S-腺苷甲硫氨酸（SAMe）的形成，S-腺苷甲硫氨酸是主要的生物甲基供体。在编码MAT的两个基因中，MAT 1A主要在成人肝脏中表达，而MAT 2A在所有肝外组织中表达。缺乏MAT 1A的小鼠肝脏SAMe含量降低，并自发发生肝细胞癌。目前的研究探讨了慢性肝SAMe缺乏对肝再生的影响。尽管有较高的基线肝染色的增殖细胞核抗原，MAT 1A基因敲除小鼠肝部分切除术（PH）后，通过溴脱氧尿苷掺入测定肝再生受损。这可以通过在敲除小鼠中PH后不能上调细胞周期蛋白D1来解释。参与细胞周期蛋白D1激活的上游信号通路包括核因子κ B（NF κ B）、c-Jun-N-末端激酶（JNK）、细胞外信号调节激酶（ERK）和信号转导和转录激活因子-3（STAT-3）。在基线时，JNK和ERK在敲除小鼠中更活化，而NF κ B和STAT-3与野生型小鼠相似。PH后，这些通路的早期激活发生，但尽管它们在野生型小鼠中仍然增加，c-jun和ERK磷酸化在敲除中逐渐下降。在野生型小鼠中，PH后肝脏SAMe水平逐渐下降，但在基因敲除小鼠中保持不变。在培养中，MAT 1A敲除肝细胞具有较高的基线DNA合成，但未能对肝细胞生长因子的促有丝分裂作用作出反应。总之，我们的研究结果定义了SAMe在ERK信号转导和细胞周期蛋白D1调控再生过程中的关键作用，并表明慢性肝SAMe耗竭导致对有丝分裂信号的反应性丧失。
Methionine adenosyltransferase (MAT) is an essential enzyme because it catalyzes the formation of S-adenosylmethionine (SAMe), the principal biological methyl donor. Of the two genes that encode MAT, MAT1A is mainly expressed in adult liver and MAT2A is expressed in all extrahepatic tissues. Mice lacking MAT1A have reduced hepatic SAMe content and spontaneously develop hepatocellular carcinoma. The current study examined the influence of chronic hepatic SAMe deficiency on liver regeneration. Despite having higher baseline hepatic staining for proliferating cell nuclear antigen, MAT1A knockout mice had impaired liver regeneration after partial hepatectomy (PH) as determined by bromodeoxyuridine incorporation. This can be explained by an inability to up-regulate cyclin D1 after PH in the knockout mice. Upstream signaling pathways involved in cyclin D1 activation include nuclear factor kappaB (NFkappaB), the c-Jun-N-terminal kinase (JNK), extracellular signal-regulated kinases (ERKs), and signal transducer and activator of transcription-3 (STAT-3). At baseline, JNK and ERK are more activated in the knockouts whereas NFkappaB and STAT-3 are similar to wild-type mice. Following PH, early activation of these pathways occurred, but although they remained increased in wildtype mice, c-jun and ERK phosphorylation fell progressively in the knockouts. Hepatic SAMe levels fell progressively following PH in wild-type mice but remained unchanged in the knockouts. In culture, MAT1A knockout hepatocytes have higher baseline DNA synthesis but failed to respond to the mitogenic effect of hepatocyte growth factor. Taken together, our findings define a critical role for SAMe in ERK signaling and cyclin D1 regulation during regeneration and suggest chronic hepatic SAMe depletion results in loss of responsiveness to mitogenic signals.