GTPase ARFRP1 Is Essential for Normal Hepatic Glycogen Storage and Insulin-Like Growth Factor 1 Secretion
GTPase ARFRP1 Is Essential for Normal Hepatic Glycogen Storage and Insulin-Like Growth Factor 1 Secretion
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DOI：
10.1128/mcb.00522-12
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发表时间：
2012-11-01
影响因子：
5.3
通讯作者：
Schuermann, Annette
中科院分区：
文献类型：
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作者：
Hesse, Deike;Jaschke, Alexander;Schuermann, Annette
GTP酶ADP-核糖化因子相关蛋白1(ARFRP1)位于跨高尔基体室，调节Arf-like 1(ARL1)及其效应子Golgin-245向该室的募集。在这里，我们发现小鼠肝脏特异的Arfrp1基因敲除(Arfrp1(Liv-/-))导致早期生长迟缓，这与肝脏胰岛素样生长因子1(IGF1)分泌减少有关。因此，抑制原代肝细胞中的Arfrp1导致IGF1的释放显著减少。然而，在没有ARFRP1的情况下，肝脏IGF结合蛋白2(IGFBP2)的分泌不受影响。此外，Arfrp1(Liv-/-)小鼠表现出葡萄糖向肝脏的转运减少，导致糖原储存减少50%，并且在禁食和重新喂养后糖原储存明显延迟。糖代谢的这些异常可归因于Arfrp1(Liv-/-)肝脏中蛋白质水平的降低和葡萄糖转运体GLUT2在细胞内的滞留。由于肝脏对葡萄糖的摄取受损，糖反应元件结合蛋白(ChREBP)及其靶基因(葡萄糖激酶和丙酮酸激酶)的表达水平显著降低。我们的数据表明，肝脏中的ARFRP1参与了IGF1分泌和GLUT2分类的调节，因此对正常生长和糖原储存是必不可少的。
The GTPase ADP-ribosylation factor-related protein 1 (ARFRP1) is located at the trans-Golgi compartment and regulates the recruitment of Arf-like 1 (ARL1) and its effector golgin-245 to this compartment. Here, we show that liver-specific knockout of Arfrp1 in the mouse (Arfrp1(liv-/-)) resulted in early growth retardation, which was associated with reduced hepatic insulin-like growth factor 1 (IGF1) secretion. Accordingly, suppression of Arfrp1 in primary hepatocytes resulted in a significant reduction of IGF1 release. However, the hepatic secretion of IGF-binding protein 2 (IGFBP2) was not affected in the absence of ARFRP1. In addition, Arfrp1(liv-/-) mice exhibited decreased glucose transport into the liver, leading to a 50% reduction of glycogen stores as well as a marked retardation of glycogen storage after fasting and refeeding. These abnormalities in glucose metabolism were attributable to reduced protein levels and intracellular retention of the glucose transporter GLUT2 in Arfrp1(liv-/-) livers. As a consequence of impaired glucose uptake into the liver, the expression levels of carbohydrate response element binding protein (ChREBP), a transcription factor regulated by glucose concentration, and its target genes (glucokinase and pyruvate kinase) were markedly reduced. Our data indicate that ARFRP1 in the liver is involved in the regulation of IGF1 secretion and GLUT2 sorting and is thereby essential for normal growth and glycogen storage.