Supplementation of Rice Bran Oil (RBO) into diet demonstrated a hypolipidemic effect on experimental rat, but the mechanism is still not well understood. We tested the effect RBO on lipid metabolism in rats induced by high-fat diet (HFD) and compare it with orlistat. Sprague-Dawley male rats at seven-week-old were fed on HFD diets (45% fat) for 28 days and divided into a control group (NaCl 0.9%), ORL group (Orlistat 10.8 mg/kg bw/day), and RBO group (RBO contain 57.6 mg oryzanol/day). Supplementation were given through oral gavage. Blank group was given standard diet (10% fat). Body weight and gene expression examination were demonstrated. Data are expressed as the mean ± SEM. One-way ANOVA were used where applicable. Student’s t test was used to analyze the differences between two groups. Compared to the blank group, the three HFD groups exhibited higher body weight; however, there were no differences in cumulative feed intake and final body weight among the four groups. Microarray analysis on liver identified that RBO altered the expression of PPARα target genes, which include Stearoyl-CoA Desaturase 1 (Scd1) and family acyl-CoA thioesterases (Acot). Both ORL and RBO groups elevate the expression of Scd1 for > 2 fold, but reduce Acot5 expression. These finding suggest RBO is as effective as orlistat in preventing hyperlipidaemia and steatosis by reducing hepatic ER stress.