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Effects of exogenous DLK1 administration on the hepatic steatosis and fibrosis in two different murine models

Other Titles
 DLK1의 투여가 지방간의 발생 및 섬유화에 미치는 효과 
Authors
 김현민 
Department
 Dept. of Internal Medicine (내과학교실) 
Issue Date
2016
Description
Dept. of Medicine/박사
Abstract
Notch signaling activation is involved in development and progression of lipogenesis and fibrosis in liver, and results in various spectrums of non-alcoholic fatty liver disease (NAFLD). One of the endogenous inhibitors of Notch signaling, Delta-like 1 homolog (DLK1), is widely expressed in developing tissues. Recent finding showed the effect of DLK1 on modulating adipogenesis and muscle development. Therefore, we investigated the effect of exogenous DLK1 in vitro and in vivo on the development or progression of NAFLD.
A soluble DLK1 peptide was generated with fusion between a human Fc fragment and extracellular domain of DLK1. DLK1 were treated in the db/db mice and methionine and choline deficient (MCD) diet–fed mice for 4 weeks. HepG2 and LX-2 cells were used for in vitro experiments.
After exogenous 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 AMP-activated protein kinase (AMPK) in hepatocytes and increasing fatty acid oxidation in liver. Furthermore, DLK1-treated MCD diet-fed mice showed significantly lower levels steatosis and fibrosis, with decreased hepatocyte apoptosis compared with the vehicle-treated group. In activated LX-2 cells, DLK1 treatment increased AMPK activation, reduced TGF-β/Smad2/3 phosphorylation, and decreased fibrogenic gene expression. Furthermore, DLK1 treatment prevented hepatocyte apoptosis by AMPK activation in HepG2 cells.
In conclusion, this study demonstrated that exogenous administration of DLK1 reduced hepatic steatosis, fibrosis, and apoptosis by AMPK activation. These results suggest that DLK1 may be a novel therapeutic approach for treating NAFLD.
Files in This Item:
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Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 3. Dissertation
Yonsei Authors
Kim, Hyun Min(김현민)
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/149164
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