Abstract: Objective To explore the protective effect and mechanism of selenium on rat model of simple fatty liver induced by high-fat diet. Methods A total of 40 SPF SD rats were randomly divided into the normal control group (NC), the model control group (HF), the low-dose group of selenium (L-SE, 0.5 mg/kg) and the high-dose group of selenium (H-SE, 1.0 mg/kg). The effects of selenium on body weight, serum TC, TG, HDL-C, LDL-C, ALT, AST, TC, TG, protein lipase (LPL) and hepatic lipase (HL) activity was recorded. The histopathological changes of liver tissues were observed by HE and oil red O staining, and the average area of fat cells of epididymal fat was calculated. RT-PCR was used to determine the mRNA expression of PPAR relationships, C/EBP relationships, SREBP-1c and SREBP-2 in each group. Results After application of selenium (0.5-1.0 mg/kg), the rat serum TG, LDL-C, ALT, AST and liver index level significantly decreased, and hepatic lipase activity increased significantly. RT-RCR showed that selenium element down-regulated significantly SREBP-1c and C/EBPα mRNA expression, up-regulated the expression of PPAR αm RNA (all P < 0.05), but no obvious effect on the expression of SREBP-2 mRNA. Application of selenium significantly reduced hepatauxe of rats, improved the fatty degeneration of hepatocytes, and inhibited the increase of epididymal adipose tissue. Conclusion Application of selenium can pay an important role in the prevention and treatment of simple fatty liver through correcting dyslipidemia and improving liver function and hepatic steatosis. Its mechanism may be related to the up-regulation of PPARα mRNA expression, down-regulation of C/EBPα and SREBP-1c mRNA expression, and improvement of the activity of hepatic lipase, which can further increase the TG decomposition and lower TG synthesis.