Both authors contributed equally to the manuscript.
Metabolic and Steatohepatitis
GLP-1 analogue prevents NAFLD in ApoE KO mice with diet and Acrp30 knockdown by inhibiting c-JNK
Article first published online: 24 FEB 2013
© 2013 John Wiley & Sons A/S
Volume 33, Issue 5, pages 794–804, May 2013
How to Cite
Liver Int. 2013: 33: 794–804
- Issue published online: 7 APR 2013
- Article first published online: 24 FEB 2013
- Accepted manuscript online: 25 JAN 2013 12:40PM EST
- Manuscript Accepted: 9 JAN 2013
- Manuscript Received: 12 JUL 2012
- National Natural Science Foundation of China. Grant Numbers: 30871199, 81070640, 30971388 and 30771037
- Doctoral Fund of Ministry of Education of China. Grant Number: 20105503110002
- Natural Science Foundation Key Project of CQ cstc. Grant Number: cstc2012 jjB10008
- Special Foundation for Postdoctoral Project of CQ. Grant Number: Yu xm201103004
- the American Diabetes Association grant. Grant Number: 1-10-CT-06
- JNK pathway;
- Non-alcoholic fatty liver disease;
- proinflammatory stress
Background & Aims
Liraglutide, a Glucagon-like peptide-1(GLP-1) analogue with 97% sequence identity to human GLP-1, increases insulin secretion and insulin sensitivity. Its effect on non-alcoholic fatty liver disease (NAFLD) remains poorly understood. In this study, we examined whether liraglutide can protect against inflammatory stress by inhibiting activation of c-Jun N-terminal protein kinase (JNK).
ApoE KO and adiponectin (Acrp30) knockdown mice fed a high-fat diet (HFD) were treated with liraglutide (1 mg/kg, twice daily) for 8 weeks. Liver tissue was procured for histological examination, real-time RT-PCR and Western blot analysis.
The results showed that the combination of HFD, Acrp30 knockdown and ApoE deficiency had additive effects on the development of insulin resistance (IR) and NAFLD. Administration of liraglutide prevented the development of HFD and hypoadiponectinaemia–induced IR and NAFLD in this model. Liraglutide also attenuated the expression of proinflammatory cytokines or transcription factor, including TNF-α and NF-κB65, and the expression of two lipogenesis-related genes, Acetyl-CoA Carboxylase (ACC) and fatty acid synthase (FAS). These changes were accompanied by elevated plasma of Acrp30, increased Acrp30 mRNA, AMP Kinase phosphorylation, and decreased mitogen-activated protein kinase 4 (MKK4) mRNA expression and JNK phosphorylation.
Our study also showed potent inhibitory effects of liraglutide on MKK4/JNK signalling which may be a mechanism for the observed improved insulin sensitivity and inflammatory stress induced by HFD and hypoadiponectinaemia.