Liraglutide attenuates palmitate-induced apoptosis via PKA/ß-catenin/Bcl-2/Bax pathway in MC3T3-E1 cells.

Liraglutide (LRG), one agonist of glucagon-like peptide-1 receptor (GLP1R), has multiple lipid-lowering effects in type 2 diabetes mellitus, however, studies on the role of LRG in saturated fatty acid-induced bone loss are limited. Therefore, our aim was to investigate whether LRG reduces palmitate (PA)-induced apoptosis and whether the mechanism involves PKA/ß-catenin/Bcl-2/Bax in osteoblastic MC3T3-E1 cells. MC3T3-E1 cells were treated with different concentrations of PA, LRG, or pretreated with Exendin 9-39 and H89, cell viability, intracellular reactive oxygen species (ROS), cAMP levels, apoptosis and the expression of protein kinase A (PKA) and phosphorylation of PKA (p-PKA), ß-catenin and phosphorylation of ß-catenin (Ser675)(p-ß-catenin), GLP1R, cleaved-capase 3, Bcl2-Associated X Protein (Bax) and B-cell lymphoma-2 (Bcl-2) along with expression of Osteoprotegerin (OPG) and receptor activator of nuclear factor-κB ligand (RANKL) were evaluated. PA treatment inhibited cell proliferation and cAMP levels, elevated intracellular ROS levels and promoted apoptosis, increased protein expressions of RANKL, Bax and cleaved-caspase3, meanwhile decreased protein expression of OPG and Bcl-2 in a dose-dependent manner. LRG inverted PA-induced apoptosis, increased cAMP levels, promoted expression of p-PKA, p-ß-catenin (Ser675) and reversed these gene expressions via increasing GLP1R expression. Pretreatment of the cells with Exendin 9-39 and H89 partially eradicated the protective effect of LRG on PA-induced apoptosis and gene expressions. Therefore, these findings indicated that LRG attenuates PA-induced apoptosis possibly by GLP1R-mediated PKA/ß-catenin/Bcl-2/Bax pathway in MC3T3-E1 cells. Our results point to LRG as a new strategy to attenuate bone loss associated with high fat diet beyond its lipid-lowering actions. LRG inhibits PA-mediated apoptosis via GLP1R-mediated PKA/ß-catenin/Bcl-2/ Bax pathway, while possibly enhances PA-inhibited differentiation by regulating the expression of OPG and RANKL.