Potential role of lycopene in targeting proprotein convertase subtilisin/kexin type-9 to combat hypercholesterolemia

Free Radic Biol Med. 2017 Jul;108:394-403. doi: 10.1016/j.freeradbiomed.2017.04.012. Epub 2017 Apr 12.


Proprotein convertase subtilisin/kexin type 9 (PCSK-9) is a serine protease of the proprotien convertase (PC) family that has profound effects on plasma low density lipoprotein cholesterol (LDL-C) levels, the major risk factor for coronary heart disease (CHD), through its ability to mediate LDL receptor (LDL-R) protein degradation and reduced recycling to the surface of hepatocytes. Thus, the current study was premeditated not only to evaluate the role of lycopene in targeting the inhibition of PCSK-9 via modulation of genes involved in cholesterol homeostasis in HFD rats but also to examine a correlation between HFD induced inflammatory cascades and subsequent regulation of PCSK-9 expression. Besides the effect of lycopene on hepatic PCSK-9 gene expression, PPI studies for PCSK-9-Lycopene complex and EGF-A of LDL-R were also performed via molecular informatics approach to assess the dual mode of action of lycopene in LDL-R recycling and increased removal of circulatory LDL-C. We for the first time deciphered that lycopene treatment significantly down-regulates the expression of hepatic PCSK-9 and HMGR, whereas, hepatic LDL-R expression was significantly up-regulated. Furthermore, lycopene ameliorated inflammation stimulated expression of PCSK-9 via suppressing the expression of inflammatory markers. The results from our molecular informatics studies confirmed that lycopene, while occupying the active site of PCSK-9 crystal structure, reduces the affinity of PCSK-9 to complex with EGF-A of LDL-R, whereas, atorvastatin makes PCSK-9-EGF-A complex formation more feasible than both of PCSK-9-EGF-A alone and Lycopene-PCSK-9-EGF-A complex. Based on above results, it can be concluded that lycopene exhibits potent hypolipidemic activities via molecular mechanisms that are either identical (HMGR inhibition) or distinct from that of statins (down-regulation of PCSK-9 mRNA synthesis). To the best of our knowledge, this is the first report that lycopene has this specific biological property. Being a natural, safer and alternative therapeutic agent, lycopene could be used as a complete regulator of cholesterol homeostasis and ASCVD.

Keywords: Atherosclerosis and cytokines; HMG-CoA Reductase; LDL-receptor; Lycopene; Proprotein convertase subtilisin/kexin type-9 (PCSK-9).

MeSH terms

  • Animals
  • Antioxidants / pharmacology*
  • Antioxidants / therapeutic use
  • Carotenoids / pharmacology*
  • Carotenoids / therapeutic use
  • Cells, Cultured
  • Cholesterol, LDL / metabolism*
  • Coronary Disease / drug therapy*
  • Crystallography, X-Ray
  • Hepatocytes / drug effects
  • Hepatocytes / physiology*
  • Homeostasis
  • Hypercholesterolemia / drug therapy*
  • Lycopene
  • Male
  • Proprotein Convertase 9 / genetics
  • Proprotein Convertase 9 / metabolism*
  • Proteolysis
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, LDL / metabolism
  • Risk
  • Signal Transduction


  • Antioxidants
  • Cholesterol, LDL
  • Receptors, LDL
  • Carotenoids
  • PCSK9 protein, rat
  • Proprotein Convertase 9
  • Lycopene