Osthole Improves Insulin Resistance And Its Possible Mechanisms In Fatty Liver Rats

Aim: To determine whether osthole could improve the insulin resistance (IR) in high-fat and high-sucrose-induced fatty liver rats and to investigate its potential mechanisms.Methods: Male SD rats were used and randomly divided into the control, model group, osthole 5 and 10 mg/kg groups, positive drugs lipanthyl 30 mg/kg and rosiglitazone 4 mg/kg groups. The rat model was established by orally feeding high-fat and high-sucrose emulsion by gavage for 9 weeks. These medications were taken orally for 4 weeks after oral high-fat and high-sucrose emulsion for 6 weeks. Finally, all of the rats were sacrificed. The total cholesterol (TC), triglycerides (TG) and free fatty acids (FFA) in serum and hepatic tissue, fasting blood glucose (FBG), fasting serum insulin (FINS), serum adiponectin and liver weight were measured. The homeostasis model assessment of insulin resistance (HOMA-IR) and coefficient of hepatic weight were calculated. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were measured to evaluate the degree of hepatic damage. The histopathological changes of livers were also examined. The mRNA expressions of carnitine palmitoyltransferase 1A (CPT-1), fatty acid synthase (FAS), diacylglycerol acyltransferase (DGAT), and sterol regulatory element binding protein-1c (SREBP-1c) in the liver, and glucose transporter-4 (GLUT-4) in skeletal muscle were determined by reverse transcription-polymerase chain reaction (RT-PCR) method.Results: After treatment with osthole 5 and 10 mg/kg for 4 weeks, the serum levels of TC, TG and FFA and the contents of TG and FFA in hepatic tissue were significantly lowered(P<0.05 or P<0.01), the body weight gain was also lowered in osthole 10 mg/kg(P<0.05). But the significant difference in the hepatic TC content and liver index was not found. Moreover, the histological evaluation of liver specimens demonstrated that the steatosis and inflammation in liver in osthole-treated groups were improved, especially in the 10 mg/kg group (P<0.05). Importantly, the levels of serum FBG, FINS and HOMA-IR in the osthole 10 mg/kg group were significantly decreased (P<0.01). And the serum adiponectin level in the osthole-treated groups was increased (P<0.05) as well. RT-PCR results showed that osthole could significantly decrease the mRNA expressions of DGAT, SREBP-1c and FAS in hepatic tissue in fatty liver rats(P<0.05 or P<0.01), increase the mRNA expressions of CPT-1A(P<0.01)in hepatic tissue and GLUT-4(P<0.01) in skeletal muscle.Conclusion: Osthole could improve the IR induced by high-fat and high-sucrose emulsion in fatty liver rats, and its mechanism might be associated with activation of PPARα/γ, including subsequent reduction of DGAT, SREBP-1c and FAS gene expression, and increment of CPT-1A and GLUT-4 gene expressions via adiponectin release.