Nakamichi Sachie, Senga Yoko, Inoue Hiroshi, Emi Aki, Matsuki Yasushi, Watanabe Eijiro, Hiramatsu Ryuji, Ogawa Wataru, Kasuga Masato
Division of Diabetes, Metabolism, and Endocrinology, Department of Internal Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan.
J Mol Endocrinol. 2009 Feb;42(2):161-9. doi: 10.1677/JME-08-0145. Epub 2008 Dec 5.
Gene related to anergy in lymphocytes (GRAIL) is an E3 ubiquitin ligase that regulates energy in T-lymphocytes. Whereas, the relevance of GRAIL to T lymphocyte function is well established, the role of this protein in other cell types remains unknown. Given that GRAIL is abundant in the liver, we investigated the potential function of GRAIL in nutrient metabolism by generating mice in which the expression of GRAIL is reduced specifically in the liver. Adenovirus-mediated transfer of a short hairpin RNA specific for GRAIL mRNA markedly reduced the amounts of GRAIL mRNA and protein in the liver. Blood glucose levels of the mice with hepatic GRAIL deficiency did not differ from those of control animals in the fasted or fed states. However, these mice manifested glucose intolerance in association with a normal increase in plasma insulin levels during glucose challenge. The mice also manifested an increase in the serum concentration of free fatty acids, whereas the serum levels of cholesterol and triglyceride were unchanged. The hepatic abundance of mRNAs for glucose-6-phosphatase, catalytic (a key enzyme in hepatic glucose production) and for sterol regulatory element-binding transcription factor 1 (an important transcriptional regulator of lipogenesis) was increased in the mice with hepatic GRAIL deficiency, possibly contributing to the metabolic abnormalities of these animals. Our results thus demonstrate that GRAIL in the liver is essential for maintenance of normal glucose and lipid metabolism in living animals.
淋巴细胞失能相关基因（GRAIL）是一种E3泛素连接酶，可调节T淋巴细胞的能量。尽管GRAIL与T淋巴细胞功能的相关性已得到充分证实，但该蛋白在其他细胞类型中的作用仍不清楚。鉴于GRAIL在肝脏中含量丰富，我们通过培育肝脏中GRAIL表达特异性降低的小鼠，研究了GRAIL在营养代谢中的潜在功能。腺病毒介导的针对GRAIL mRNA的短发夹RNA的转移显著降低了肝脏中GRAIL mRNA和蛋白的含量。肝脏GRAIL缺乏的小鼠在禁食或进食状态下的血糖水平与对照动物没有差异。然而，这些小鼠在葡萄糖刺激期间表现出葡萄糖不耐受，同时血浆胰岛素水平正常升高。这些小鼠还表现出血清游离脂肪酸浓度升高，而胆固醇和甘油三酯的血清水平未发生变化。肝脏GRAIL缺乏的小鼠中，葡萄糖-6-磷酸酶催化亚基（肝脏葡萄糖生成中的关键酶）和固醇调节元件结合转录因子1（脂肪生成的重要转录调节因子）的mRNA在肝脏中的丰度增加，这可能导致了这些动物的代谢异常。因此，我们的结果表明，肝脏中的GRAIL对于活体动物维持正常的葡萄糖和脂质代谢至关重要。
