Histone Deacetylase SIRT1 Controls Proliferation, Circadian Rhythm, and Lipid Metabolism during Liver Regeneration in Mice
Histone Deacetylase SIRT1 Controls Proliferation, Circadian Rhythm, and Lipid Metabolism during Liver Regeneration in Mice
复制标题
DOI：
10.1074/jbc.m116.737114
复制
发表时间：
2016-10-28
影响因子：
4.8
通讯作者：
Servillo, Giuseppe
中科院分区：
文献类型：
--
作者：
Bellet, Marina Maria;Masri, Selma;Servillo, Giuseppe
肝脏再生为研究体内细胞增殖提供了独特的机会。哺乳动物沉默信息调节因子 1 (SIRT1) 是一种 NAD(+) 依赖性组蛋白脱乙酰酶，是多种细胞过程的重要调节因子，包括增殖、代谢和昼夜节律。在肝脏中，SIRT1 协调时钟控制基因的昼夜节律振荡，包括编码参与代谢途径的酶的基因。我们对 WT 和肝脏特异性 Sirt1 缺陷小鼠进行了部分肝切除术，并通过实时 PCR、蛋白质印迹分析和免疫组织化学分析了再生过程中不同时间采集的肝脏样本中细胞周期调节因子的表达。通过 MS/HPLC 对相同样品进行脂质组学分析。我们发现肝脏中缺乏 SIRT1 以及昼夜节律基因表达会显着影响 G(1)/S 进展。这与脂肪酸β-氧化缺陷导致的脂质积累有关。我们的研究首次揭示了 SIRT1 在小鼠肝再生过程中调节肝细胞增殖、昼夜节律和脂质代谢的重要性。这些结果表明 SIRT1 在肝脏中的功能表征又向前迈出了一步。
Liver regeneration offers a distinctive opportunity to study cell proliferation in vivo. Mammalian silent information regulator 1 (SIRT1), a NAD(+)-dependent histone deacetylase, is an important regulator of various cellular processes, including proliferation, metabolism, and circadian rhythms. In the liver, SIRT1 coordinates the circadian oscillation of clock-controlled genes, including genes that encode enzymes involved in metabolic pathways. We performed partial hepatectomy in WT and liver-specific Sirt1-deficient mice and analyzed the expression of cell cycle regulators in liver samples taken at different times during the regenerative process, by real time PCR, Western blotting analysis, and immunohistochemistry. Lipidomic analysis was performed in the same samples by MS/HPLC. We showed that G(1)/S progression was significantly affected by absence of SIRT1 in the liver, as well as circadian gene expression. This was associated to lipid accumulation due to defective fatty acid beta-oxidation. Our study revealed for the first time the importance of SIRT1 in the regulation of hepatocellular proliferation, circadian rhythms, and lipid metabolism during liver regeneration in mice. These results represent an additional step toward the characterization of SIRT1 function in the liver.