Yan, Xin and Wang, Zhen and Bishop, Christopher A. and Weitkunat, Karolin and Feng, Xiao and Tarbier, Marcel and Luo, Jiankai and Friedlander, Marc R. and Burkhardt, Ralph and Klaus, Susanne and Willnow, Thomas E. and Poy, Matthew N. (2018) Control of hepatic gluconeogenesis by Argonaute2. MOLECULAR METABOLISM, 18. pp. 15-24. ISSN 2212-8778,
Full text not available from this repository. (Request a copy)Abstract
Objective: The liver performs a central role in regulating energy homeostasis by increasing glucose output during fasting. Recent studies on Argonaute2 (Ago2), a key RNA-binding protein mediating the microRNA pathway, have illustrated its role in adaptive mechanisms according to changes in metabolic demand. Here we sought to characterize the functional role of Ago2 in the liver in the maintenance of systemic glucose homeostasis. Methods: We first analyzed Ago2 expression in mouse primary hepatocyte cultures after modulating extracellular glucose concentrations and in the presence of activators or inhibitors of glucokinase activity. We then characterized a conditional loss-of-function mouse model of Ago2 in liver for alterations in systemic energy metabolism. Results: Here we show that Ago2 expression in liver is directly correlated to extracellular glucose concentrations and that modulating glucokinase activity is adequate to affect hepatic Ago2 levels. Conditional deletion of Ago2 in liver resulted in decreased fasting glucose levels in addition to reducing hepatic glucose production. Moreover, loss of Ago2 promoted hepatic expression of AMP-activated protein kinase alpha 1 (AMPK alpha 1) by de-repressing its targeting by miR-148a, an abundant microRNA in the liver. Deletion of Ago2 from hyperglycemic, obese, and insulin-resistant Lep(ob/ob) mice reduced both random and fasted blood glucose levels and body weight and improved insulin sensitivity. Conclusions: These data illustrate a central role for Ago2 in the adaptive response of the liver to fasting. Ago2 mediates the suppression of AMPKa1 by miR-148a, thereby identifying a regulatory link between non-coding RNAs and a key stress regulator in the hepatocyte. (C) 2018 The Authors. Published by Elsevier GmbH.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | RNA-BINDING PROTEINS; GLUCOSE-METABOLISM; MICRORNAS; LIVER; PHOSPHORYLATION; IDENTIFICATION; HOMEOSTASIS; EXPRESSION; COMPLEXES; HEALTH; RNA-binding proteins; Energy homeostasis; Glucose metabolism; Metabolic stress; microRNAs; Cellular adaptation |
| Subjects: | 500 Science > 540 Chemistry & allied sciences 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Klinische Chemie und Laboratoriumsmedizin |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 07 Oct 2019 06:50 |
| Last Modified: | 07 Oct 2019 06:50 |
| URI: | https://pred.uni-regensburg.de/id/eprint/13461 |
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