Short chain fatty acids (SCFAs) are produced in the colonic lumen mainly by bacterial fermentation of dietary fiber. Emerging evidence shows that SCFA has important physiological and pathophysiological effects on colonic and systemic events. Recently, propionate, known as a kind of SCFA, has been shown to lower fatty acid contents in plasma and reduce food intake. However, the detailed mechanism underlying the propionate-mediated lipid metabolism action remains poorly understood. The intestinal lipid metabolism process is critical for systemic energy homeostasis. Therefore, we investigate here the effects of propionate on intestinal lipid metabolism. Results show that propionate induced peroxisome proliferator-activated receptor α (PPARα) expression time-dependently and concentration-dependently in YAMC (a mouse intestinal epithelial cell line) cells. The expression levels of PPARα-responsive genes such as carnitine palmitoyl transferase II (CPTII) and trifunctional protein α (TFPα) were up-regulated in the presence of propionate, thereby suppressing triglyceride (TG) accumulation. Furthermore, propionate-mediated PPARα induction required phosphorylation of extracellular signal-regulated kinase. Collectively, these data indicate that propionate regulates intestinal lipid metabolism through the induction of PPARα expression. Results suggest that the inhibitory effect of propionate on TG accumulation partly contributes to the propionate-mediated fatty acid-lowering effect.