Osthole improves fat milk-induced fatty liver in rats: Modulation of hepatic PPAR-alpha/gamma-mediated lipogenic gene expression

The objectives of this study were to determine the therapeutic effect of osthole, an active constituent isolated from Cnidium monnieri (L.) Cusson (Apiaceae), in hyperlipidemic fatty liver (HFL) rats and investigate the possible mechanism of the osthole treatment. The HFL rat model was established by feeding Sprague-Dawley rats with fat milk for 6 weeks. The experimental rats were then treated with a dose of osthole of 5-20 mg/kg for 6 weeks. After the treatment, total cholesterol (TC) and triglycerides (TG) in serum and hepatic tissue, as well as the coefficient of hepatic weight were measured. The results showed that the TC and TG in both serum and hepatic tissue and the coefficient of hepatic weight in the osthole-treated rats were lower as compared to those in the experimental group, respectively (P < 0.05 or P < 0.01). Moreover, as compared to the control group, the osthole treatment increased the PPAR alpha/gamma mRNA expression by 58.0-84.0% and 20.4-77.4%, respectively. The related target genes for mRNA expression were also increased by osthole-treatment, e.g., 53.4-93.2% for CYP7A, 21.1-63.2% for L-FABP and 34.1-57.3 for FATP4, while the DGAT mRNA expression was decreased by 26.0-44.4%. The therapeutic effect of osthole was further confirmed by histological evaluation of the liver showing a dramatically decreased lipid accumulation and improved ultrastructure of hepatocytes. In conclusion, osthole exerts therapeutic effects on fat milk-induced fatty liver in rats, by regulating mRNA expression of the target genes of CYP7A, DGAT, L-FABP and FATP4 via increasing the PPAR alpha/gamma mRNA expression.