Glucagon‐like peptide 1 (GLP‐1) is a naturally occurring peptide secreted by the L cells of the small intestine. GLP‐1 functions as an incretin and stimulates glucose‐mediated insulin production by pancreatic β cells. In this study, we demonstrate that exendin‐4/GLP‐1 has a cognate receptor on human hepatocytes and that exendin‐4 has a direct effect on the reduction of hepatic steatosis in the absence of insulin. Both glucagon‐like peptide 1 receptor (GLP/R) messenger RNA and protein were detected on primary human hepatocytes, and receptor was internalized in the presence of GLP‐1. Exendin‐4 increased the phosphorylation of 3‐phosphoinositide‐dependent kinase‐1 (PDK‐1), AKT, and protein kinase C ζ (PKC‐ζ) in HepG2 and Huh7 cells. Small interfering RNA against GLP‐1R abolished the effects on PDK‐1 and PKC‐ζ. Treatment with exendin‐4 quantitatively reduced triglyceride stores compared with control‐treated cells. Conclusion: This is the first report that the G protein–coupled receptor GLP‐1R is present on human hepatocytes. Furthermore, it appears that exendin‐4 has the same beneficial effects in vitro as those seen in our previously published in vivo study in ob/ob mice, directly reducing hepatocyte steatosis. Future use for human nonalcoholic fatty liver disease, either in combination with dietary manipulation or other pharmacotherapy, may be a significant advance in treatment of this common form of liver disease. (HEPATOLOGY 2010)