3 years ago

GLP-1 Analogue, Exendin-4, Modulates MAPKs Activity but not the Heat Shock Response in Human HepG2 Cells

Abdelkrim Khadir, Ali Tiss, Maha Hammad, Sina Kavalakatt, Dhanya Madhu
Purpose : Glucagon-like peptide-1 (GLP-1) analogues reduce ER stress and inflammation in key metabolic organs, including the liver. However, their effects on heat shock response (HSR) and mitogen-activated protein kinases (MAPKs) have not yet been elucidated. In the present study, we investigated whether the GLP-1 analogue, exendin-4, triggers the expression of HSR and increases MAPK activity under metabolic stress. Experimental design : The effects of exendin-4 in the presence or absence of palmitic acid (PA; 400 μM) or glucose (30 mM) in the HepG2 liver cell line were assessed using Western blots, quantitative real-time PCR and label-free proteomics. Results : Heat shock proteins (HSP60, HSP72, HSP90 and GRP78) and other chaperones were not significantly affected by exendin-4 under the conditions tested. In contrast, the presence of exendin-4 alone increased the MAPK phosphorylation levels (JNK, ERK1/2 and p38). For short incubation periods, in the presence of PA or glucose, treatment with exendin-4 exhibited limited effects but significantly attenuated MAPK phosphorylation after a 24-h incubation. Interestingly, canonical signalling pathways, such as EIF2, ILK, PKA and Rho, were modulated by exendin-4. Conclusion and clinical relevance : Identifying new pathways modulated by GLP-1 analogues will provide further insights into their benefits beyond their currently recognized roles in glycaemic control, such as MAPK activity, energy homeostasis and body weight decrease. This article is protected by copyright. All rights reserved

Publisher URL: http://onlinelibrary.wiley.com/resolve/doi

DOI: 10.1002/prca.201600169

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