title: GTPase ARFRP1 is essential for normal hepatic glycogen storage and insulin-like growth factor 1 secretion.
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 (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.
authors.affiliation: Department of Experimental Diabetology, German Institute of Human Nutrition Potsdam-Rehbruecke, Nuthetal, Germany.
authors.forename: Deike
authors.initials: D
authors.lastname: Hesse
authors.forename: Alexander
authors.initials: A
authors.lastname: Jaschke
authors.forename: Timo
authors.initials: T
authors.lastname: Kanzleiter
authors.forename: Nicole
authors.initials: N
authors.lastname: Witte
authors.forename: Robert
authors.initials: R
authors.lastname: Augustin
authors.forename: Angela
authors.initials: A
authors.lastname: Hommel
authors.forename: Gerhard Paul
authors.initials: GP
authors.lastname: Püschel
authors.forename: Klaus-Jürgen
authors.initials: KJ
authors.lastname: Petzke
authors.forename: Hans-Georg
authors.initials: HG
authors.lastname: Joost
authors.forename: Michael
authors.initials: M
authors.lastname: Schupp
authors.forename: Annette
authors.initials: A
authors.lastname: Schürmann
mesh_terms: D020727:ADP-Ribosylation Factors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D050260:Carbohydrate Metabolism; D049109:Cell Proliferation; D002478:Cells, Cultured; D005947:Glucose / Q000378:metabolism; D051273:Glucose Transporter Type 2 / Q000378:metabolism*; D006056:Golgi Apparatus / Q000378:metabolism; D022781:Hepatocytes / Q000378:metabolism; D018971:Insulin-Like Growth Factor Binding Protein 2 / Q000096:biosynthesis / Q000378:metabolism; D007334:Insulin-Like Growth Factor I / Q000096:biosynthesis / Q000378:metabolism*; D008099:Liver / Q000378:metabolism*; D008112:Liver Glycogen / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009687:Nuclear Proteins / Q000096:biosynthesis; D034622:RNA Interference; D034741:RNA, Small Interfering; D014157:Transcription Factors / Q000096:biosynthesis
chemical_list: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D051273:Glucose Transporter Type 2; D018971:Insulin-Like Growth Factor Binding Protein 2; D008112:Liver Glycogen; C506001:Mlxipl protein, mouse; D009687:Nuclear Proteins; D034741:RNA, Small Interfering; C495682:Slc2a2 protein, mouse; D014157:Transcription Factors; C519530:insulin-like growth factor-1, mouse; D007334:Insulin-Like Growth Factor I; D020727:ADP-Ribosylation Factors; C531986:Arfrp1 protein, mouse; D005947:Glucose