Department of Medical Biochemistry, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan.
Department of Medical Biochemistry, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan; Department of Metabolic Medicine, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan.
Cell Metab. 2014 Apr 1;19(4):712-21. doi: 10.1016/j.cmet.2014.03.006.
Sirtuins (SIRT1-7) have attracted considerable attention as regulators of metabolism over the past decade. However, the physiological functions and molecular mechanisms of SIRT7 are poorly understood. Here we demonstrate that Sirt7 knockout mice were resistant to high-fat diet-induced fatty liver, obesity, and glucose intolerance, and that hepatic triglyceride accumulation was also attenuated in liver-specific Sirt7 knockout mice. Hepatic SIRT7 positively regulated the protein level of TR4/TAK1, a nuclear receptor involved in lipid metabolism, and as a consequence activated TR4 target genes to increase fatty acid uptake and triglyceride synthesis/storage. Biochemical studies revealed that the DDB1-CUL4-associated factor 1 (DCAF1)/damage-specific DNA binding protein 1 (DDB1)/cullin 4B (CUL4B) E3 ubiquitin ligase complex interacted with TR4, leading to its degradation, while binding of SIRT7 to the DCAF1/DDB1/CUL4B complex inhibited the degradation of TR4. In conclusion, we propose that hepatic SIRT7 controls lipid metabolism in liver by regulating the ubiquitin-proteasome pathway.
过去十年间，沉默调节蛋白（SIRT1-7）作为代谢调节剂受到了广泛关注。然而，SIRT7 的生理功能和分子机制仍知之甚少。本研究表明 Sirt7 敲除小鼠对高脂肪饮食诱导的脂肪肝、肥胖和葡萄糖不耐受具有抗性，且特异性敲除肝脏 Sirt7 也可减轻肝内三酰甘油的积累。肝脏 SIRT7 正向调控参与脂代谢的核受体 TR4/TAK1 的蛋白水平，进而激活 TR4 靶基因以增加脂肪酸摄取和三酰甘油的合成/储存。生化研究表明 DDB1-CUL4 相关因子 1（DCAF1）/损伤特异性 DNA 结合蛋白 1（DDB1）/CUL4B 连接酶复合物与 TR4 相互作用，导致其降解，而 SIRT7 与 DCAF1/DDB1/CUL4B 复合物结合可抑制 TR4 的降解。综上，我们提出肝脏 SIRT7 通过调控泛素蛋白酶体通路来控制肝脏的脂质代谢。
