SIRT1 controls liver regeneration by regulating bile acid metabolism through farnesoid X receptor and mammalian target of rapamycin signaling.
SIRT1 controls liver regeneration by regulating bile acid metabolism through farnesoid X receptor and mammalian target of rapamycin signaling.
复制标题
DOI：
10.1002/hep.26971
复制
发表时间：
2014-05
期刊：
影响因子：
13.5
通讯作者：
Luz Martinez-Chantar, Maria
中科院分区：
文献类型：
--
作者：
Garcia-Rodriguez, Juan L.;Barbier-Torres, Lucia;Fernandez-Alvarez, Sara;Gutierrez-de Juan, Virginia;Monte, Maria J.;Halilbasic, Emina;Herranz, Daniel;Alvarez, Luis;Aspichueta, Patricia;Marin, Jose J. G.;Trauner, Michael;Mato, Jose M.;Serrano, Manuel;Beraza, Naiara;Luz Martinez-Chantar, Maria
Sirtuin1(SIRT1)通过去乙酰化作用调节脂肪生成、蛋白质合成、糖异生和胆汁酸(BA)动态平衡等中枢代谢功能。在这里，我们描述SIRT1严格控制肝脏的再生反应。我们对过表达SIRT1(SIRT)的转基因小鼠进行了部分肝切除(PH)。Sirt组小鼠术后死亡率增加，肝细胞增殖受损，BA蓄积，肝损伤加重。SIRT小鼠的损伤表型与FXR活性受损有关，这是由于持续的脱乙酰基和低蛋白表达导致FXR靶基因表达减少；SHP、BSEP和Cyp7A1增加。接下来，我们令人信服地表明，24-去甲去氧胆酸(NorUDCA)减弱了SIRT蛋白的表达，增加了FXR和邻近组蛋白的乙酰化，恢复了H3K4和H3K9的三甲基化，并增加了miR34a的表达，从而重建了BA的动态平衡。结果，NorUDCA恢复了SIRT小鼠的肝再生，表现出增加了存活率和肝细胞增殖。此外，富含亮氨酸的饲料恢复了mTOR的激活、FXR和组蛋白的乙酰化，通过SHP抑制Cyp7A1而导致整体BA产量较低，而较高的转运(BSEP)和解毒(Sult2a1)导致肝脏再生得到改善。最后，我们发现人类肝癌样本中SIRT1的存在增加，这与FXR的缺失相关，表明其具有致癌潜力。总体而言，我们将SIRT1定义为通过转录后修饰调节FXR、组蛋白和mTOR的活性，从而调节肝脏再生反应的关键调节因子。此外，我们的数据表明，SIRT1通过持续的FXR去乙酰化来调节BA的动态平衡，从而参与肝脏肿瘤的发生。
Sirtuin1 (SIRT1) regulates central metabolic functions such as lipogenesis, protein synthesis, gluconeogenesis and bile acid (BA) homeostasis through deacetylation. Here, we describe that SIRT1 tightly controls the regenerative response of the liver. We performed partial hepatectomy (PH) to transgenic mice that overexpress SIRT1 (SIRT). SIRT mice showed increased mortality, impaired hepatocyte proliferation, BA accumulation and profuse liver injury after surgery. The damaging phenotype in SIRT mice correlated with impaired FXR activity due to persistent deacetylation and lower protein expression that led to decreased FXR-target gene expression; SHP, BSEP and increased Cyp7A1. Next, we convincingly show that 24-norUrsodeoxycholic acid (NorUDCA) attenuates SIRT protein expression, increases the acetylation of FXR and neighboring histones, restores trimethylation of H3K4 and H3K9 and increases miR34a expression, thus re-establishing BA homeostasis. Consequently, NorUDCA restored liver regeneration in SIRT mice, which showed increased survival and hepatocyte proliferation. Furthermore, a Leucine-enriched diet restored mTOR activation, acetylation of FXR and histones, leading to an overall lower BA production through SHP-inhibition of Cyp7A1 and higher transport (BSEP) and detoxification (Sult2a1) leading to an improved liver regeneration. Finally, we found that human HCC samples have increased presence of SIRT1, which correlated with absence of FXR suggesting its oncogenic potential. Overall, we define SIRT1 as a key regulator of the regenerative response in the liver through post-transcriptional modifications that regulate the activity of FXR, histones and mTOR. Moreover, our data suggest that SIRT1 contributes to liver tumorigenesis through dysregulation of BA homeostasis by persistent FXR deacetylation.
登录
查看更多内容
影响因子：
16
作者：
Sengupta S;Peterson TR;Sabatini DM
通讯作者：
Sabatini DM
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：
Fang, Sungsoon;Tsang, Stephanie;Kemper, Jongsook Kim
通讯作者：
Kemper, Jongsook Kim
影响因子：
64.8
作者：
Rodgers, JT;Lerin, C;Puigserver, P
通讯作者：
Puigserver, P
影响因子：
13.5
作者：
Jin, Jingling;Iakova, Polina;Jiang, Yanjun;Medrano, Estela E.;Timchenko, Nikolai A.
通讯作者：
Timchenko, Nikolai A.