Extra Virgin Olive Oil Phenol Extracts Exert Hypocholesterolemic Effects through the Modulation of the LDLR Pathway: In Vitro and Cellular Mechanism of Action Elucidation

This study was aimed at investigating the hypocholesterolemic eects of extra virgin olive oil (EVOO) phenols and the mechanisms behind the eect. Two phenolic extracts were prepared from EVOO of dierent cultivars and analyzed using the International Olive Council (IOC) ocial method for total phenols, a recently validated hydrolytic procedure for total hydroxytyrosol and tyrosol, and 1H-NMR analysis in order to assess their secoiridoid profiles. Both of the extracts inhibited in vitro the 3-hydroxy-3-methylglutaryl co-enzyme A reductase (HMGCoAR) activity in a dose-dependent manner. After the treatment of human hepatic HepG2 cells (25 g/mL), they increased the low-density lipoprotein (LDL) receptor protein levels through the activation of the sterol regulatory element binding proteins (SREBP)-2 transcription factor, leading to a better ability of HepG2 cells to uptake extracellular LDL molecules with a final hypocholesterolemic eect. Moreover, both of the extracts regulated the intracellular HMGCoAR activity through the increase of its phosphorylation by the activation of AMP-activated protein kinase (AMPK)-pathways. Unlike pravastatin, they did not produce any unfavorable eect on proprotein convertase subtilisin/kexin 9 (PCSK9) protein level. Finally, the fact that extracts with dierent secoiridoid profiles induce practically the same biological eects suggests that the hydroxytyrosol and tyrosol derivatives may have similar roles in hypocholesterolemic activity.