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Inhibition of proprotein convertase subtilisin/kexin type 9: a novel mechanism of berberine and 8-hydroxy dihydroberberine against hyperlipidemia.

AbstractOBJECTIVE:
To investigate the effect and molecular mechanisms of different doses of 8-hydroxy dihydroberberine (Hdber) for the treatment of hyperlipidemia in rats.
METHODS:
A rat model of hyperlipidemia was established by feeding rats a high-fat diet for 4 weeks in 70 rats of 80 animals, and 10 rats were randomly selected as control group. The hyperlipidemic rats were then randomly divided into the following groups: a model group (MOD); a berberine group [BBR, 156 mg/(kg day)]; Hdber groups, which were treated with different doses of Hdber [78, 39 and 19.5 mg/(kg day)]; and a simvastatin group [SIM, 4 mg/(kg day)]. The corresponding therapy was administered to the rats of each treatment via gastric tubes. Normal animals were used as a control group. The blood levels of various lipids, including total cholesterol, triglycerides, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, free fatty acid (FFA), apolipoprotein AI(Apo-AI) and apolipoprotein B (Apo-B) were examined. The protein expressions of low-density lipoprotein receptor (LDL-R), sterol regulatory element-binding protein 2 (SREBP-2), 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR) and proprotein convertase subtilisin/kexin type 9 (PCSK-9) in liver tissues were determined by Western blot analysis.
RESULTS:
Compared with the control group of rats, the model group demonstrated a deteriorated blood lipid profile and exhibited increased expression levels of PCSK-9 protein in their liver tissues (P<0.01). In addition, the high-fat diet decreased the expression levels of LDL-R, SREBP-2 and HMGCR proteins in murine liver tissues. However, the addition of berberine or Hdber reversed the blood lipid profile changes (P<0.05 or P<0.01), decreased the expression levels of PCSK-9 proteins (P<0.01), and increased the expression levels of LDL-R proteins in the hyperlipidemic rats (P<0.01). These compounds did not significantly influence the expression levels of SREBP-2 and HMGCR proteins in the hyperlipidemic rats.
CONCLUSIONS:
Hdber is effective in the treatment of hyperlipidemia in rats. The therapeutic mechanisms of Hdber may be associated with increasing the expression of LDL-R protein and decreasing the expression of PCSK-9 protein in liver tissues.
AuthorsDe-liang Liu, Li-jun Xu, Hui Dong, Guang Chen, Zhao-yi Huang, Xin Zou, Kai-fu Wang, Yun-huan Luo, Fu-er Lu
JournalChinese journal of integrative medicine (Chin J Integr Med) Vol. 21 Issue 2 Pg. 132-8 (Feb 2015) ISSN: 1672-0415 [Print] China
PMID24893659 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Apolipoprotein A-I
  • Apolipoproteins B
  • Lipids
  • Receptors, LDL
  • Sterol Regulatory Element Binding Protein 2
  • Berberine
  • dihydroberberine
  • Hydroxymethylglutaryl CoA Reductases
  • PCSK9 protein, rat
  • Proprotein Convertase 9
  • Serine Endopeptidases
Topics
  • Animals
  • Apolipoprotein A-I (blood)
  • Apolipoproteins B (blood)
  • Berberine (analogs & derivatives, pharmacology, therapeutic use)
  • Hydroxymethylglutaryl CoA Reductases (metabolism)
  • Hyperlipidemias (blood, drug therapy)
  • Lipids (blood)
  • Liver (drug effects, metabolism)
  • Male
  • Proprotein Convertase 9
  • Rats, Wistar
  • Receptors, LDL (metabolism)
  • Serine Endopeptidases (metabolism)
  • Sterol Regulatory Element Binding Protein 2 (metabolism)

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