Department of Metabolomics, CIC bioGUNE, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (Ciberehd), Technology Park of Bizkaia, Bizkaia, Spain.
Hepatology. 2014 May;59(5):1972-83. doi: 10.1002/hep.26971. Epub 2014 Mar 31.
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 farnesoid X receptor (FXR) activity due to persistent deacetylation and lower protein expression that led to decreased FXR-target gene expression; small heterodimer partner (SHP), bile salt export pump (BSEP), and increased Cyp7A1. Next, we 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 reestablishing BA homeostasis. Consequently, NorUDCA restored liver regeneration in SIRT mice, which showed increased survival and hepatocyte proliferation. Furthermore, a leucine-enriched diet restored mammalian target of rapamycin (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 hepatocellular carcinoma (HCC) samples have increased presence of SIRT1, which correlated with the absence of FXR, suggesting its oncogenic potential.
We define SIRT1 as a key regulator of the regenerative response in the liver through posttranscriptional 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.
Sirtuin1（SIRT1）通过去乙酰化调节中央代谢功能，如脂肪生成、蛋白质合成、糖异生和胆汁酸（BA）稳态。在这里，我们描述了 SIRT1 紧密控制肝脏的再生反应。我们对过表达 SIRT1（SIRT）的转基因小鼠进行部分肝切除术（PH）。SIRT 小鼠表现出更高的死亡率、受损的肝细胞增殖、BA 积累和大量肝损伤。SIRT 小鼠的损伤表型与法尼醇 X 受体（FXR）活性受损相关，这是由于持续去乙酰化和更低的蛋白质表达导致 FXR 靶基因表达降低；小异二聚体伴侣（SHP）、胆汁盐输出泵（BSEP）和 Cyp7A1 增加。接下来，我们表明 24-降乌索脱氧胆酸（NorUDCA）可减弱 SIRT 蛋白表达，增加 FXR 和邻近组蛋白的乙酰化，恢复 H3K4 和 H3K9 的三甲基化，并增加 miR34a 表达，从而重新建立 BA 稳态。因此，NorUDCA 恢复了 SIRT 小鼠的肝再生，提高了它们的存活率和肝细胞增殖率。此外，亮氨酸富集饮食恢复了哺乳动物雷帕霉素靶蛋白（mTOR）的激活、FXR 和组蛋白的乙酰化，导致 Cyp7A1 被 SHP 抑制和更高的转运（BSEP）和解毒（Sult2a1）的整体较低的 BA 产生，从而改善肝再生。最后，我们发现人类肝细胞癌（HCC）样本中 SIRT1 的存在增加，与 FXR 的缺失相关，表明其致癌潜能。
我们将 SIRT1 定义为通过调节 FXR、组蛋白和 mTOR 活性的转录后修饰来调节肝脏再生反应的关键调节剂。此外，我们的数据表明，SIRT1 通过持续的 FXR 去乙酰化导致 BA 稳态失调，促进肝肿瘤发生。
