Objective Non-alcholic fatty liver disease (NAFLD) is associated with insulin resistance, and metabolic syndrome. To reverse the NAFLD is helpful for treatment of insulin resistance condition. Recently many extrapancreatic effects of GLP-1 have been demonstrated. But, the direct effect of GLP-1 receptor agonist, exendin-4 (EX-4) on the liver is not clear. Therefore we investigated the direct effect of GLP-1 on the lipid metabolism in HEP3B cell line and in the liver of high fat (HF) fed dbdb mice. Methods GLP-1 receptor was confirmed by realtime PCR and confocal microscopy in the HEP3B cell and Dbdb mice liver. HEP3B cell was treated with 0.5 mM palmitate with or without 100 nM exenitide treatment. 10 μg/kg Ex-4 was injected i.p to the HF fed dbdb mice for 6 weeks. Saline treatment mice and pair-feeding mice were control group. The mRNA expression of gene associated with lipid metabolism was examined by real time PCR. The protein expression was studied by Western blot. Results EX-4 reduced fat accumulation and reduced lipogenic gene such as SREBP-1, DGAT-1 and increased the gene exression of fatty acid beta oxidation such as CPT-1, PPAR-alpha in HEP3B cell treated with 0.5 mM palmitate and HF fed dbdb mice. EX-4 could not reverse the autophagy induced by palmitate in the HEP3B and high fat fed mice. Conclusion In conclusion, GLP-1 receptor agonist, EX-4 reduced hepatic fat accumulation through down regulation of lipogenic gene expression and up-regulation of lipid oxidation gene, rather than autophagy pathway.