Mice lacking thyroid hormone receptor Beta show enhanced apoptosis and delayed liver commitment for proliferation after partial hepatectomy.
Mice lacking thyroid hormone receptor Beta show enhanced apoptosis and delayed liver commitment for proliferation after partial hepatectomy.
复制标题
DOI：
10.1371/journal.pone.0008710
复制
发表时间：
2010-01-14
期刊：
影响因子：
3.7
通讯作者：
Boscá L
中科院分区：
文献类型：
--
作者：
López-Fontal R;Zeini M;Través PG;Gómez-Ferrería M;Aranda A;Sáez GT;Cerdá C;Martín-Sanz P;Hortelano S;Boscá L
应用遗传学和药理学方法研究了甲状腺激素及其受体（TR）在肝部分切除（PH）后肝再生中的作用。T3在肝再生中的作用已被提出，但没有明确的证据区分T3增加量的贡献与未占用TR的调节。缺乏TRα1/TRβ或单独TRβ的小鼠在PH后完全再生肝块，但在PH后48小时显示延迟的肝细胞增殖的初始阶段和短暂但强烈的凋亡，影响约30%的剩余肝细胞。药理学诱导的甲状腺功能减退也产生了类似的结果。TR活性的损失与增强的亚硝化应激在肝脏残体，由于一氧化氮合酶（NOS）2和3的活性增加，引起的不对称二甲基精氨酸（ADMA），一种有效的NOS抑制剂的浓度的瞬时下降。ADMA水平的降低是由于在缺乏TRα1/TRβ或TRβ的动物的再生肝脏中存在较高活性的二甲基精氨酸氨基水解酶-1（DDAH-1）。DDAH-1的表达和活性受到FXR活性的影响，FXR是一种参与肝再生的转录因子，在TR缺失的情况下上调。我们报告TR不是肝再生所必需的;然而，甲状腺功能减退小鼠和TRβ或TRα1/TRβ缺陷小鼠表现出肝质量恢复延迟，表明TRβ在肝再生中的特定作用。再生反应的改变与细胞周期蛋白D1和E的表达延迟以及在缺乏激活的TRβ的情况下发生肝细胞凋亡有关，这可以通过给予NOS抑制剂来预防。综上所述，这些结果表明TRβ显著促进PH后肝细胞的快速初始增殖，并改善后期再生肝的存活。
The role of thyroid hormones and their receptors (TR) during liver regeneration after partial hepatectomy (PH) was studied using genetic and pharmacologic approaches. Roles in liver regeneration have been suggested for T3, but there is no clear evidence distinguishing the contribution of increased amounts of T3 from the modulation by unoccupied TRs. Mice lacking TRα1/TRβ or TRβ alone fully regenerated liver mass after PH, but showed delayed commitment to the initial round of hepatocyte proliferation and transient but intense apoptosis at 48h post-PH, affecting ∼30% of the remaining hepatocytes. Pharmacologically induced hypothyroidism yielded similar results. Loss of TR activity was associated with enhanced nitrosative stress in the liver remnant, due to an increase in the activity of the nitric oxide synthase (NOS) 2 and 3, caused by a transient decrease in the concentration of asymmetric dimethylarginine (ADMA), a potent NOS inhibitor. This decrease in the ADMA levels was due to the presence of a higher activity of dimethylarginineaminohydrolase-1 (DDAH-1) in the regenerating liver of animals lacking TRα1/TRβ or TRβ. DDAH-1 expression and activity was paralleled by the activity of FXR, a transcription factor involved in liver regeneration and up-regulated in the absence of TR. We report that TRs are not required for liver regeneration; however, hypothyroid mice and TRβ– or TRα1/TRβ–deficient mice exhibit a delay in the restoration of liver mass, suggesting a specific role for TRβ in liver regeneration. Altered regenerative responses are related with a delay in the expression of cyclins D1 and E, and the occurrence of liver apoptosis in the absence of activated TRβ that can be prevented by administration of NOS inhibitors. Taken together, these results indicate that TRβ contributes significantly to the rapid initial round of hepatocyte proliferation following PH, and improves the survival of the regenerating liver at later times.
登录
查看更多内容
影响因子：
13.5
作者：
Fausto, N;Campbell, JS;Riehle, KJ
通讯作者：
Riehle, KJ
影响因子：
4.8
作者：
Pibiri, M;Ledda-Columbano, GM;Columbano, A
通讯作者：
Columbano, A
影响因子：
25.7
作者：
Fausto, N
通讯作者：
Fausto, N
影响因子：
6.7
作者：
Kariv, R;Enden, A;Oren, R
通讯作者：
Oren, R
影响因子：
56.9
作者：
Huang, WD;Ma, K;Moore, DD
通讯作者：
Moore, DD