Abstract
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 (Arfrp1liv−/−) 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, Arfrp1liv−/− 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 Arfrp1liv−/− 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.
ACKNOWLEDGMENTS
We are grateful to Mark Magnusson, Center for Stem Cell Biology, Vanderbilt University Medical Center, Nashville, TN, for providing the Alb-Cre. The skillful technical assistance of Michaela Rath, Andrea Teichmann, Kathrin Warnke, Anna Rusaczonek, and Elisabeth Meyer is gratefully acknowledged.
This work was supported by the German Research Foundation (Schu 750/5-3, SFB 958), the German Ministry of Education and Research (BMBF, DZD, grant 01GI0922) and European Community's 7 FB Prepobedia (grant 201681). M.S. is supported by the German Research Foundation Emmy-Noether (Schu 2546/1-1).