Glucagon-like peptide-1 receptor mediates the improvement in glycolipid metabolism disorder via AKT and AMPK signalling pathways in L02 cells with insulin resistance

Abstract Background: Glucagon like peptide 1 (GLP-1) has previously been found to regulate glycolipid metabolism in the liver by promoting insulin secretion. However, the direct regulation of GLP-1 on liver glycolipid metabolism was still controversial, due to the presence of GLP-1 receptors (GLP-1R) in human liver has not been determined. In this research, the presence and direct effect on hepatic metabolism of GLP-1R were investigated in L02 cells (normal human hepatocytes).Methods: The insulin resistance cell model with metabolic disorder was constructed using oleic acid and fructose to simulate the metabolic syndrome caused by high-fat and high-fructose in modern diet. Glycolipid metabolism markers and the involvement of AMP-activated protein kinase (AMPK) and PI3 Kinase (PI3K)-AKT were assessed.Results: GLP-1R was found to be expressed in L02 cells and decreased in insulin resistance cells. GLP-1R knockdown induced a dramatic decrease in glucose utilization and intracellular content, and increase in mRNA levels of genes associated with gluconeogenesis via AKT pathway independent of PI3K. Furthermore, GLP-1R knockdown increased the contents of triglyceride (TG) and total cholesterol (TC) by increasing the mRNA levels of sterol response element binding protein-1c (SREBP-1c), fatty acid synthase (FAS) and acetyl CoA carboxylase (ACC), and decreasing the mRNA level of carnitine palmitoyl transferase 1 (CPT-1) via AMPK pathway.Conclusions: GLP-1R mediated the LG-caused promotion of glucose utilization and inhibition of lipid synthesis, as the positive effects of LG were diminished by GLP-1R knockdown. These findings demonstrated that GLP-1R is the molecular basis for GLP-1 to improve glycolipid metabolism in L02 cells.