AIM: To investigate the preventive and therapeutic effects of sesamin (SES) on fatty liver disease in rats with hypertension combined with dyslipidemia, and to explore the potential mechanisms based on mRNA-seq. METHODS: Spontaneously hypertensive rats (SHRs) were fed a high-fat, high-cholesterol diet to establish a rat model of hypertension combined with dyslipidemia, and then treated with SES for 16 weeks continuously. The experiment was divided into four groups: WKY, SHR, Model, and Model+SES (160 mg·kg-1·d-1). Blood pressure was measured using the tail-cuff method. Body weight was monitored, and body mass index was calculated. Liver morphology was detected by ultrasound, and liver thickness was measured. Liver wet weight was weighed, and liver index was calculated. Liver volume was detected by the water displacement method. Serum triglycerides (TG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), alanine aminotransferase (ALT), aspartate aminotransferase (AST), and total bile acids (TBA) were detected by ELISA. Liver sequencing analysis was performed using mRNA-seq. Liver histomorphological changes were observed by HE staining. The degree of hepatic steatosis was observed by Oil Red O staining, and the degree of hepatic fibrosis was observed by MASSON staining. The mRNA expression of Aldh1a7, Nnmt, Irs2, Pltp, and Scd was detected by q-PCR. The protein expression of Scd, Nnmt, AMPK, p-AMPK, PPARα, and PPARγ was detected by Western blotting. RESULTS: After 16 weeks of continuous SES administration to rats with hypertension combined with dyslipidemia, blood pressure was significantly reduced (P<0.01), and body weight was decreased. Serum TG, TC, and LDL-C levels were decreased, while HDL-C levels were increased. Serum ALT and AST levels were decreased. Liver weight, organ index, liver thickness, and liver volume were decreased. The degree of hepatic steatosis and hepatic fibrosis was improved. A total of 545 differentially expressed mRNAs were identified in the livers of rats in each group, of which 278 were upregulated and 267 were downregulated. Among the 27 commonly differentially expressed mRNAs, five mRNAs related to lipid metabolism were screened, namely Aldh1a7, Nnmt, Irs2, Pltp, and Scd. KEGG enrichment analysis showed that the enriched pathways were AMPK and PPAR. Further validation revealed that in the SES-treated group, the mRNA expression of Scd in the liver was decreased, while the mRNA expression of Nnmt was increased. The protein expression of Scd was decreased, while the protein expression of Nnmt, AMPK, p-AMPK, PPARα, and PPARγ was increased. CONCLUSION: SES has preventive and therapeutic effects on fatty liver disease in rats with hypertension combined with dyslipidemia, and its mechanism of action may be related to the reduction of Scd expression levels in the liver and the increase in the expression of Nnmt, AMPK, p-AMPK, PPARα, and PPARγ.