Keratinocyte growth factor (KGF) is a member of the fibroblast growth factor family that was originally identified as a keratinocyte mitogen after isolation from a lung fibroblast cell line. In this study, we demonstrate that administration of KGF to mice and rats elevates serum lipid levels. In rats, 1 h after KGF administration, serum triglyceride and FFA levels were increased, with peak values at 2 h (1.9-fold increase). The increase in serum triglyceride levels was sustained for at least 16 h. Serum cholesterol levels were also increased, but the effect was delayed beginning at 4 h, with peak values at 16 h (1.27-fold increase). KGF did not decrease the clearance of triglyceride-rich lipoproteins, but increased hepatic triglyceride secretion. KGF stimulated lipolysis, but not hepatic de novo fatty acid synthesis, and the increased delivery of FFA to the liver plays a crucial role in the KGF-induced hypertriglyceridemia. Neither alpha- nor beta-adrenergic receptor antagonists affected the hypertriglyceridemia induced by KGF, indicating that endogenous catecholamines are not involved in mediating KGF-induced hypertriglyceridemia. These results demonstrate that KGF induces hypertriglyceridemia by increasing hepatic triglyceride secretion, with the fatty acids provided by lipolysis making a major contribution. Thus, KGF could modulate lipid metabolism in vivo.