Objective

2

To observe the expression of hepatocyte nuclear factor 1

α

（HNF1

α

）， proprotein convertase subtilisin/kexin type 9 （PCSK9） and low-density lipoprotein cholesterol （LDLR） in hypercholesterolemia rat liver， and investigate the mechanism of Shuangyu Tiaozhi Decoction regulating cholesterol metabolism and attenuating hypercholesterolemia.

Method

2

After providing a high-fat diet for 4 weeks， 40 SD rats were selected， 8 of which were randomly selected as normal group and fed a normal diet， and the remaining 32 rats were fed a high-fat diet. The rats successfully established as hypercholesterolemic model， were randomized into 4 groups： model group， low dose of Shuangyu Tiaozhi decoction group （7.8 g·kg

-1

）， high dose of Shuangyu Tiaozhi decoction group （15.6 g·kg

-1

）， and simvastatin group （4 mg·kg

-1

）， with 8 rats in each group. The drugs were continuously given for 8 weeks. Serum total cholesterol （TC）， triglyceride （TG）， low-density lipoprotein cholesterol （LDL-C）， high-density lipoprotein cholesterol （HDL-C） were measured. The pathomorphological changes in liver were observed by hematoxylin and eosin （HE） staining. The immunohistochemistry was used to detect PCSK9 and LDLR expression in liver. The mRNA and protein expression levels of HNF1

α

， PCSK9 and LDLR were determined by Real-time fluorescence quantitative polymerase chain reaction （Real-time PCR） and Western blot.

Result

2

Compared with normal group， the TC， TG， LDL-C levels in model group were significantly increased （

P

<

0.01）， the morphology showed obvious liver steatosis. The mRNA and protein expression of HNF1

α

and PCSK9 were increased （

P

<

0.05）， the mRNA and protein expression of LDLR was decreased （

P

<

0.05）. Compared with model group， the serum TC， TG， LDL-C levels were significantly lowered in the Shuangyu Tiaozhi decoction high-dose group （

P

<

0.01）， the serum TC， LDL-C levels were significantly lowered in the Shuangyu Tiaozhi decoction low-dose group and simvastatin group （

P

<

0.05，

P

<

0.01）， while no significant effect was observed on the serum HDL-C levels in each treatment group. The liver steatosis decreased in each treatment group. The mRNA and protein expression of HNF1

α

was obviously decreased in each treatment group （

P

<

0.05，

P

<

0.01）， the mRNA and protein expression of PCSK9 was obviously decreased in Shuangyu Tiaozhi decoction low and high-dose groups （

P

<

0.05，

P

<

0.01）， the mRNA expression of PCSK9 was significantly increased in the simvastatin group （

P

<

0.01）， while the protein expression showed a downward trend. The LDLR mRNA levels were significantly increased in each treatment group （

P

<

0.01）， the LDLR protein expression was significantly increased in Shuangyu Tiaozhi high-dose group （

P

<

0.01）， and showed an upward trend in Shuangyu Tiaozhi low-dose group and simvastatin group. Results of immunohistochemistry showed PCSK9 expression was weakly positive， the expression of LDLR was strongly positive in each treatment group. The therapeutic effect of Shuangyu Tiaozhi decoction high-dose group was more remarkable than simvastatin group， while there was no obvious difference between the Shuangyu Tiaozhi decoction low-dose group and simvastatin group.

Conclusion

2

Shuangyu Tiaozhi decoction may reduce the blood lipid levels through HNF1

α

/PCSK9/LDLR signaling pathway， play an active role on regulating cholesterol metabolism and alleviating high-fat diet-induced hypercholesterolemia.