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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.
Reconstructing how rivers respond to changes in runoff or sediment supply by incising or aggrading has been pivotal in gauging the role of the Indian Summer Monsoon (ISM) as a geomorphic driver in the Himalayas. Here we present new chronological data for fluvial aggradation and incision from the Donga alluvial fan and the upper Alaknanda River, as well as a compilation of previous work. In addition to conventional OSL-SAR (Single-Aliquot Regenerative-Dose) dating method, we have tested and applied pulsed OSL (POSL) dating for quartz samples that include K-rich feldspar inclusions, which is expected to improve the applicability and validity of OSL ages in the Lesser Himalaya. For previously dated deposits, our OSL ages are shown to be systematically older than previously reported ages. These results suggest periods of aggradation in the Alaknanda and Dehradun Valleys mainly between similar to 25 and 35 ka. This most likely reflects decreased stream power during periods of weakened monsoon. In addition, in-situ cosmogenic beryllium-10 was used to infer bedrock surface exposure ages, which are interpreted as episodes of active fluvial erosion. Resulting exposure ages span from 3 to 6 ka, suggesting that strath terraces were exposed relatively recently, and incision was dominant through most of the Holocene. In combination, our results support precipitation-driven fluvial dynamics, which regulates the balance between stream power and sediment supply. On a larger spatial scale, however, fluvial dynamics are probably not spatially homogeneous as aggradation could have been taking place in adjacent catchments while incision dominated in the study area. (C) 2018 Elsevier Ltd. All rights reserved.