[Glucagon-like peptide-1 regulates lipid metabolism in hepatocytes through Foxo1/3]

Objective: Glucagon-like peptide-1 (GLP-1) has been reported to be effective in the treatment of nonalcoholic fatty liver disease (NAFLD). However, the molecular mechanism of GLP-1 on NAFLD is remained unclear. The present study was to detect whether the effect of GLP-1 on triglyceride (TG) content in hepatocytes is dependent on Foxos. Methods: HepG2 cells were treated with palmitic/oleic acid for 24 h. The knockdown of Foxo1, Foxo3 was conducted through small interfering RNA (siRNA). Real time PCT (RT-PCR) was used to detect the changes of the SREBP1c and Acox2 genes in HepG2 cells after Foxo1/3 knockdown. Results: As expected, palmitic/oleic acid increased TG concentration in HepG2 cells [(12.65 ± 1.32) μg/mg vs. (4.32±0.54) μg/mg, P<0.05]. Addition of GLP-1 dose (10, 50, 100nmol/L) dependently lowered the TG content and reached plateau at 100 nmol/L of GLP-1 [TG(8.38±1.47) μg/mg]. The GLP-1 effect on TG remained after knocking down either Foxo1 [(9.09±1.34)μg/mg] or Foxo3 [(8.90±1.60) μg/mg] alone, but not when knocking down Foxo1 and Foxo3 (Foxo1/3) together [(14.66±1.77)μg/mg]. Moreover, knocking down Foxo1/3 also abolished GLP-1 effect on SREBP1c and Acox2 expression. Conclusion: GLP-1 can inhibit the synthesis of TG in hepatocytes depending on Foxo1 and Foxo3. Further studies are needed to explore the specific mechanisms.