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GLP ‐1 analogue prevents NAFLD in ApoE KO mice with diet and Acrp30 knockdown by inhibiting c‐ JNK
Author(s) -
Zhang Lili,
Yang Mengliu,
Ren Hong,
Hu Huaidong,
Boden Guenther,
Li Ling,
Yang Gangyi
Publication year - 2013
Publication title -
liver international
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.873
H-Index - 110
eISSN - 1478-3231
pISSN - 1478-3223
DOI - 10.1111/liv.12120
Subject(s) - liraglutide , endocrinology , adiponectin , medicine , insulin resistance , fatty acid synthase , proinflammatory cytokine , gene knockdown , lipogenesis , insulin , protein kinase a , kinase , biology , chemistry , adipose tissue , diabetes mellitus , type 2 diabetes , inflammation , biochemistry , lipid metabolism , apoptosis
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 ). 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 MKK 4/ JNK signalling which may be a mechanism for the observed improved insulin sensitivity and inflammatory stress induced by HFD and hypoadiponectinaemia.