Shimizu Yusuke I, Morita Momoko, Ohmi Asako, Aoyagi Shun, Ebihara Hitomi, Tonaki Daijuro, Horino Yoko, Iijima Mika, Hirose Hidenori, Takahashi Shigeru, Takahashi Yuji
Laboratory of Environmental Molecular Physiology, School of Life Sciences, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo 192-0392, Japan.
Life Sci. 2009 Jun 19;84(25-26):894-902. doi: 10.1016/j.lfs.2009.04.002. Epub 2009 Apr 17.
Food deprivation (fasting) is commonly encountered in the lives of animals and humans. In mammals, adaptive responses predominantly include the induction of hepatic gluconeogenesis, but the regulatory mechanisms remain unclear. Atf5 (activating transcription factor 5) is a transcription factor of the ATF/cAMP response element-binding protein family and is expressed abundantly in human liver. Atf5 has been associated with stress responses, cell differentiation, proliferation, and survival. However, its role in the liver response to in vivo food deprivation has not yet been investigated.
Adult mice were food-deprived for 48 h and the expression of two Atf5 mRNA subtypes (Atf5-R1 and Atf-R2) and gluconeogenic factors was investigated. Using in vitro cell culture, Pgc-1alpha (peroxisome proliferator-activated receptor-gamma coactivator-1alpha) promoter activities after ectopic expression of Atf5 and Cebpg (CCAAT/enhancer-binding protein gamma) proteins were measured.
The Atf5-R1 transcript was found to be abundant in liver and other energy metabolism-related organs; Atf5-R2 was prominent in the testis. Fasting resulted in elevation of the expression of both Atf5-R1 and R2 in the liver. Interestingly, up-regulation of Atf5 was accompanied by increased expression of Cebpg and Pgc-1alpha. In human hepatoma cells (HepG2), but not in human cervical carcinoma cells (HeLa), forced expression of Atf5 and Cebpg cooperatively stimulated Pgc-1alpha promoter activity, suggesting that hepatic Pgc-1alpha could be induced by Atf5 and Cebpg in cooperation with other hepatic factors.
Hepatic Atf5 might be potentially involved in the induction of gluconeogenetic factors during in vivo fasting stress.
食物剥夺（禁食）在动物和人类生活中普遍存在。在哺乳动物中，适应性反应主要包括诱导肝脏糖异生，但调节机制仍不清楚。激活转录因子5（Atf5）是ATF/cAMP反应元件结合蛋白家族的转录因子，在人类肝脏中大量表达。Atf5与应激反应、细胞分化、增殖和存活有关。然而，其在肝脏对体内食物剥夺反应中的作用尚未得到研究。
对成年小鼠进行48小时食物剥夺，研究两种Atf5 mRNA亚型（Atf5-R1和Atf-R2）和糖异生因子的表达。使用体外细胞培养，测量Atf5和CCAAT/增强子结合蛋白γ（Cebpg）蛋白异位表达后过氧化物酶体增殖物激活受体γ共激活因子1α（Pgc-1α）启动子活性。
发现Atf5-R1转录本在肝脏和其他能量代谢相关器官中丰富；Atf5-R2在睾丸中突出。禁食导致肝脏中Atf5-R1和R2的表达升高。有趣的是，Atf5的上调伴随着Cebpg和Pgc-1α表达的增加。在人肝癌细胞（HepG2）中，而不是在人宫颈癌细胞（HeLa）中，Atf5和Cebpg的强制表达协同刺激Pgc-1α启动子活性，表明肝脏中的Pgc-1α可能由Atf5和Cebpg与其他肝脏因子协同诱导。
肝脏Atf5可能在体内禁食应激期间参与诱导糖异生因子。
