Department of Stress Response Science, Center for Advanced Medical Science, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki 036-8562, Japan.
Laboratory Animal Resource Center, University of Tsukuba, 1-1-1 Tennodai, Tsukuba 305-8575, Japan.
Int J Mol Sci. 2022 Mar 16;23(6):3201. doi: 10.3390/ijms23063201.
GCN1 is an evolutionarily-conserved ribosome-binding protein that mediates the amino acid starvation response as well as the ribotoxic stress response. We previously demonstrated that mutant mice lacking the GCN2-binding domain suffer from growth retardation and postnatal lethality via GCN2-independent mechanisms, while -null mice die early in embryonic development. In this study, we explored the role of GCN1 in adult mice by generating tamoxifen-inducible conditional knockout (CKO) mice. Unexpectedly, the CKO mice showed body weight loss during tamoxifen treatment, which gradually recovered following its cessation. They also showed decreases in liver weight, hepatic glycogen and lipid contents, blood glucose and non-esterified fatty acids, and visceral white adipose tissue weight with no changes in food intake and viability. A decrease of serum VLDL suggested that hepatic lipid supply to the peripheral tissues was primarily impaired. Liver proteomic analysis revealed the downregulation of mitochondrial β-oxidation that accompanied increases of peroxisomal β-oxidation and aerobic glucose catabolism that maintain ATP levels. These findings show the involvement of GCN1 in hepatic lipid metabolism during tamoxifen treatment in adult mice.
GCN1 是一种进化上保守的核糖体结合蛋白，可介导氨基酸饥饿反应以及核糖体毒性应激反应。我们之前的研究表明，缺乏 GCN2 结合域的 突变小鼠通过 GCN2 非依赖性机制遭受生长迟缓和出生后致死，而 -null 小鼠在胚胎发育早期死亡。在这项研究中，我们通过生成他莫昔芬诱导的条件性敲除（CKO）小鼠来探索 GCN1 在成年小鼠中的作用。出乎意料的是，在他莫昔芬处理期间， CKO 小鼠表现出体重减轻，停止处理后逐渐恢复。它们还表现出肝重、肝糖原和脂质含量、血糖和非酯化脂肪酸降低，以及内脏白色脂肪组织重量不变，而食物摄入量和活力没有变化。血清 VLDL 的减少表明肝脏向外周组织供应脂质的主要受损。肝脏蛋白质组学分析显示，线粒体 β-氧化的下调伴随着过氧化物酶体 β-氧化和有氧葡萄糖分解代谢的增加，这些代谢可维持 ATP 水平。这些发现表明 GCN1 参与了成年小鼠在他莫昔芬处理期间的肝脂代谢。
