Objective To investigate the mechanism of orotic acid-induced fatty liver in rats. Method Rats were randomly divided into 2 groups,and fed AIN93 diet with or without 1% orotic acid (OA) for 10d. Serum total cholesterol (TC),triglyceride (TG),high density lipoprotein-cholesterol (HDL-C),hepatic lipids concentrations (TG,TC and phospholipids),hepatic enzymes activities and mRNA levels of key enzymes related to lipids metabolism,as well as hepatic genes expression of transcription factors were determined. Results OA administration significantly increased serum and hepatic TG concentration. The activity and mRNA level of fatty acid synthase (FAS) were obviously up-regulated by OA treatment,whereas the activities and mRNA concentrations of carnitin palmitoyl transferase (CPT) and microsomal triglyceride transfer protein (MTP) were depressed significantly. Furthermore,OA also stimulated the mRNA expression of sterol regulatory element binding protein-1c (SREBP-1c),but did not alter the mRNA concentrations of peroxisome proliferator-activated receptor alpha (PPAR?) in liver. Conclusion:The stimulation of TG synthesis caused by enhancement of SREBP-1c and its target genes-FAS,which could be responsible for development of fatty liver. On the other hand,the inhibition of fatty acid beta-oxidation and VLDL secretion were related to the observed lipids accumulation.