The Effect And Mechanism Of Pentamethylquercetin On Metabolic Disorder And NAFLD In DIO Mice

Obesity induced by high fat diet(HFD) is one of the most common DIO models. This model shows an apparent obesity phenotype and metabolism disorder, insulin resistance and liver lesions, et al. PMQ is one of natural polymethoxylated flavones. Our previous results have shown PMQ ameliorates NAFLD in MSG-IO mice. In this study, we build an obesity model induced by high fat diet and study the effect of PMQ on NAFLD and its possible mechanism.PartⅠ The model establishment of DIO induced by high fat dietObjective: To establish the model of DIO model induced by high fat diet.Methods: 5-week-old C57 / BL6 male mice were randomly divided in 2 groups: normal group(NFD), model group(HFD). Normal diet and high fat diet were given to NFD mice and HFD mice respectively, and all groups were allowed to eat and drink ad libitum. Body weights and weight gains were recorded every week. OGTT were measured at 22 weeks of age and all the mice were sacrificed at 24 week of age. Liver pathological condition and serum factors level were tested. The m RNA expressions of mouse liver metabolism-related factors were detected by RT-PCR.Results:(1) Mice developed obesity significantly induced by high fat diet. Body weights, waist circumference, lee index and fat content of HFD mice were increased significantly;(2) It impared glucose tolerance, and triglyceride, total cholesterol, LDL-C, fasting glucose had a significant increase. Liver pathological results showed the steatosis and fibrosis.(3) Compared with vehicle, the m RNA expression level were changed after high fat diet. Expression of FASN, CD36, PPARγ, PCSK9, SREBPs and TNFα were upregulated; expression of PGC1α, PGC-1β, PPARβ, SIRT6 and PTEN were downregulated.Conclusion: DIO mice had obvious obesity phenotype, with glucose and lipid metabolism disorder, insulin resistance and liver lesions. It is the ideal model of obesity-related nonalcoholic fatty liver disease, and it will provide an ideal model for drug treatment of NAFLD and relevant pharmacodynamics research.PartⅡ The Effect and Mechanism of Pentamethylquercetin on Ameliorating NAFLD in DIO MiceObjective: To study the effect and mechanism of PMQ on NAFLD in DIO mice.Methods: 5-week-old C57 / BL6 male mice were randomly divided in 8 groups: normal group(NFD), model group(HFD), HFD + vehicle, HFD + PMQ 5, HFD + PMQ 10, HFD + PMQ 20, HFD + RSD 5, HFD + MET 300. NFD group was treated with normal diet, and the other groups with the high fat diet, while the drug of Vehicle, PMQ 5mg/kg, 10 mg/kg, 20 mg/kg, RSG 5 mg/kg, MET 300 mg/kg were given by intragastric administration in certain group, and all groups were allowed to eat and drink ad libitum. Body weights and weight gains were recorded every week. OGTT were measured at 22 weeks of age and all the mice were sacrificed at 24 weeks of age. Liver pathological condition and serum factors level were tested. The m RNA expression of mouse liver metabolism-related factor was detected by RT-PCR.Results:(1) Compared with vehicle, mice in drug-treated groups showed decreased weight gain, waist circumference and lee index.(2) Compared with vehicle, PMQ treatment(5, 10, 20mg/kg) reduced serum TC, TG, LDL-C, fasting glucose, OGTT, insulin and HOMA-IR;(3) Compared with vehicle, the m RNA expression level were changed after treatment. FASN, CD36, PCSK9, SREBPs and TNFα m RNA expression were decreased, while PGC-1α, PGC-1β, PPARβ, SIRT6 and PTEN were increased.Conclusion:(1) PMQ can ameliorate nonalcoholic fatty liver disease in DIO mice;(2)PMQ ameliorate NAFLD through the SIRT6, PPARβ and PTEN: a. PMQ-SIRT6-TNFα-SREBPsPCSK9/FASN; b. PMQ-SIRT6-PGC-1α; c. PMQ-PPARβ-SREBPs-PCSK9/FASN; d. PMQPTEN-PCSK9/FASN.