glp-1 analogue, exendin-4, modulates mapks activity but not the heat shock response in human hepg2 cells

PurposeGlucagon‐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 investigate whether the GLP‐1 analogue, exendin‐4, triggers the expression of HSR and increases MAPK activity under metabolic stress.Experimental designThe 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 are assessed using Western blots, quantitative real‐time PCR, and label‐free proteomics.ResultsHeat shock proteins (HSP60, HSP72, HSP90, and GRP78) and other chaperones are not significantly affected by exendin‐4 under the conditions tested. In contrast, the presence of exendin‐4 alone increases the MAPK phosphorylation levels (JNK, ERK1/2, and p38). For short incubation periods, in the presence of PA or glucose, treatment with exendin‐4 exhibits limited effects but significantly attenuates MAPK phosphorylation after a 24‐h incubation. Interestingly, canonical signaling pathways, such as EIF2, ILK, PKA, and Rho, are modulated by exendin‐4.Conclusion and clinical relevanceIdentifying new pathways modulated by GLP‐1 analogues will provide further insights into their benefits beyond their currently recognized roles in glycemic control, such as MAPK activity, energy homeostasis, and body weight decrease.