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Exogenous administration of DLK1 ameliorates hepatic steatosis and regulates gluconeogenesis via activation of AMPK

Authors
 Y-h Lee  ;  MR Yun  ;  HM Kim  ;  BH Jeon  ;  B-C Park  ;  B-W Lee  ;  ES Kang  ;  HC Lee  ;  YW Park  ;  B-S Cha 
Citation
 International Journal of Obesity, Vol.40(2) : 356-365, 2016 
Journal Title
 International Journal of Obesity 
ISSN
 0307-0565 
Issue Date
2016
MeSH
AMP-Activated Protein Kinases ; Animals ; Disease Models, Animal ; Gluconeogenesis ; Injections, Intraperitoneal ; Intercellular Signaling Peptides and Proteins/pharmacology* ; Lipid Metabolism ; Liver/pathology* ; Mice ; Mice, Inbred C57BL ; Non-alcoholic Fatty Liver Disease/pathology* ; Receptors, Notch/drug effects* ; Receptors, Notch/metabolism ; Signal Transduction/drug effects*
Abstract
BACKGROUND/OBJECTIVES: Activation of Notch signaling pathologically enhances lipogenesis and gluconeogenesis in the liver causing non-alcoholic fatty liver disease (NAFLD) and diabetes. Delta-like 1 homolog (DLK1), an imprinted gene that can modulate adipogenesis and muscle development in mice, was found as an inhibitory regulator of Notch signaling. Therefore, we investigated the metabolic effect of exogenous DLK1 in vitro and in vivo. SUBJECTS/METHODS: A soluble DLK1 peptide was generated with fusion between a human Fc fragment and extracellular domain of DLK1. Male db/db mice were randomly assigned to two groups: vehicle treated and DLK1-treated group (25 mg kg(-1), intraperitoneal injection, twice a week for 4 weeks). Primary mice hepatocytes and HepG2 cells were used for in vitro experiments. RESULTS: After 4 weeks of DLK1 administration, hepatic triglyceride content and lipid droplets in liver tissues, as well as serum levels of liver enzymes, were markedly decreased in db/db mice. DLK1 treatment induced phosphorylation of AMPK and ACC and suppressed nuclear expression of SREBP-1c in the mouse liver or hepatocytes, indicating regulation of fatty acid oxidation and synthesis pathways. Furthermore, DLK1-treated mice showed significantly lower levels of fasting and random glucose, with improved glucose and insulin tolerance compared with the vehicle-treated group. Macrophage infiltration and proinflammatory cytokine levels in the epididymal fat were decreased in DLK1-treated db/db mice. Moreover, DLK1 suppressed glucose production from hepatocytes, which was blocked after co-administration of an AMPK inhibitor, compound C. DLK1-treated hepatocytes and mouse liver tissues showed lower PEPCK and G6Pase expression. DLK1 triggered AKT phosphorylation followed by cytosolic translocation of FOXO1 from the nucleus in hepatocytes. CONCLUSIONS: The present study demonstrated that exogenous administration of DLK1 reduced hepatic steatosis and hyperglycemia via AMPK activation in the liver. This result suggests that DLK1 may be a novel therapeutic approach for treating NAFLD and diabetes.
Full Text
http://www.nature.com/ijo/journal/v40/n2/full/ijo2015173a.html
DOI
10.1038/ijo.2015.173
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
Yonsei Authors
강은석(Kang, Eun Seok) ORCID logo https://orcid.org/0000-0002-0364-4675
이병완(Lee, Byung Wan) ORCID logo https://orcid.org/0000-0002-9899-4992
이용호(Lee, Yong Ho) ORCID logo https://orcid.org/0000-0002-6219-4942
이현철(Lee, Hyun Chul)
차봉수(Cha, Bong Soo) ORCID logo https://orcid.org/0000-0003-0542-2854
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URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/146380
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