Tobita Takamasa, Guzman-Lepe Jorge, Takeishi Kazuki, Nakao Toshimasa, Wang Yang, Meng Fanying, Deng Chu-Xia, Collin de l'Hortet Alexandra, Soto-Gutierrez Alejandro
Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.
Department of Hepatobiliary Surgery, Peking University People's Hospital, Beijing, China.
PLoS One. 2016 Feb 18;11(2):e0149344. doi: 10.1371/journal.pone.0149344. eCollection 2016.
There are unprecedented epidemics of obesity, such as type II diabetes and non-alcoholic fatty liver diseases (NAFLD) in developed countries. A concerning percentage of American children are being affected by obesity and NAFLD. Studies have suggested that the maternal environment in utero might play a role in the development of these diseases later in life. In this study, we documented that inhibiting SIRT1 signaling in human fetal hepatocytes rapidly led to an increase in intracellular glucose and lipids levels. More importantly, both de novo lipogenesis and gluconeogenesis related genes were upregulated upon SIRT1 inhibition. The AKT/FOXO1 pathway, a major negative regulator of gluconeogenesis, was decreased in the human fetal hepatocytes inhibited for SIRT1, consistent with the higher level of gluconeogenesis. These results indicate that SIRT1 is an important regulator of lipid and carbohydrate metabolisms within human fetal hepatocytes, acting as an adaptive transcriptional response to environmental changes.
在发达国家，肥胖、II型糖尿病和非酒精性脂肪性肝病（NAFLD）等流行病正呈前所未有的态势。美国有相当比例的儿童正受到肥胖和NAFLD的影响。研究表明，子宫内的母体环境可能在这些疾病日后的发展过程中发挥作用。在本研究中，我们记录到，抑制人类胎儿肝细胞中的SIRT1信号会迅速导致细胞内葡萄糖和脂质水平升高。更重要的是，在抑制SIRT1后，从头脂肪生成和糖异生相关基因均上调。AKT/FOXO1通路是糖异生的主要负调节因子，在受SIRT1抑制的人类胎儿肝细胞中减少，这与较高水平的糖异生一致。这些结果表明，SIRT1是人类胎儿肝细胞内脂质和碳水化合物代谢的重要调节因子，作为对环境变化的适应性转录反应发挥作用。
