LAUSR

Abstract 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. Graphical abstract Figure. No Caption available. HighlightsLycopene combats hypercholesterolemia via down‐regulating the expression of hepatic PCSK‐9 and HMGR.Lycopene increases LDL‐R gene expression and functionality to combat with high LDL‐C.Lycopene reduces the affinity of PCSK‐9 to bind with EGF‐A of LDL‐R.Lycopene negatively regulates inflammation induced PCSK‐9 expression.Lycopene ameliorates plasma PON‐1 activity to enhance HDL functionality in rats.