title: GLP-1 analogue prevents NAFLD in ApoE KO mice with diet and Acrp30 knockdown by inhibiting c-JNK.
abstract: OBJECTIVE
  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).
  
  
  METHODS
  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.
  
  
  RESULTS
  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-κB(65) , 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.
  
  
  CONCLUSIONS
  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.
authors: Department of Endocrinology, the Second Affiliated Hospital, Chongqing Medical University, Chongqing, China.
authors: Lili
authors: L
authors: Zhang
authors: Mengliu
authors: M
authors: Yang
authors: Hong
authors: H
authors: Ren
authors: Huaidong
authors: H
authors: Hu
authors: Guenther
authors: G
authors: Boden
authors: Ling
authors: L
authors: Li
authors: Gangyi
authors: G
authors: Yang
mesh_terms: D052242:Adiponectin / Q000235:genetics; D000704:Analysis of Variance; D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics; D015153:Blotting, Western; D059305:Diet, High-Fat; D004789:Enzyme Activation / Q000187:drug effects*; D005234:Fatty Liver / Q000517:prevention & control*; D055785:Gene Knockdown Techniques; D052216:Glucagon-Like Peptide 1 / Q000031:analogs & derivatives* / Q000494:pharmacology; D006652:Histological Techniques; D007333:Insulin Resistance / Q000502:physiology*; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D000069450:Liraglutide; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D065626:Non-alcoholic Fatty Liver Disease; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D052242:Adiponectin; C499919:Adipoq protein, mouse; D001057:Apolipoproteins E; D000069450:Liraglutide; D052216:Glucagon-Like Peptide 1; D048031:JNK Mitogen-Activated Protein Kinases