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

Carmen Lammi,Lorenzo Cecchi,Maria Lisa Clodoveo,Maria Bellumori,Filomena Corbo,Carlotta Bollati,Nadia Mulinacci,Martina Bartolomei,Anna Arnoldi

doi:10.3390/nu12061723

Abstract

This study was aimed at investigating the hypocholesterolemic effects of extra virgin olive oil (EVOO) phenols and the mechanisms behind the effect. Two phenolic extracts were prepared from EVOO of different cultivars and analyzed using the International Olive Council (IOC) official 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 µg/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 effect. 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 effect on proprotein convertase subtilisin/kexin 9 (PCSK9) protein level. Finally, the fact that extracts with different secoiridoid profiles induce practically the same biological effects suggests that the hydroxytyrosol and tyrosol derivatives may have similar roles in hypocholesterolemic activity.

Highlights

Cardiovascular disease (CVD) is a leading cause of death worldwide and hypercholesterolemia is one of the main risk factors responsible for the development of this multifactorial disease
Among sterol regulatory element binding proteins (SREBP)-2 gene targets, the 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCoAR) is important [5]. This enzyme plays a key role in the intracellular cholesterol biosynthesis, since it is the rate controlling enzyme in the mevalonate pathway, which is regulated by the AMP-activated protein kinase (AMPK) pathway [3]
The transcription of the LDL receptor (LDLR) and the genes that are required for cholesterol and fatty acid synthesis are controlled by membrane-bound transcription factors called

Summary

Introduction

Cardiovascular disease (CVD) is a leading cause of death worldwide and hypercholesterolemia is one of the main risk factors responsible for the development of this multifactorial disease. The LDLR expression is finely tuned by changes in intracellular cholesterol and a transcription factor, known. Nutrients 2020, 12, 1723 as the sterol-responsive element binding protein-2 (SREBP-2), plays a critical role in LDLR mRNA expression [3,4]. Among SREBP-2 gene targets, the 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCoAR) is important [5]. This enzyme plays a key role in the intracellular cholesterol biosynthesis, since it is the rate controlling enzyme in the mevalonate pathway, which is regulated by the AMP-activated protein kinase (AMPK) pathway [3]. The LDLR expression and receptor protein localization at cellular membranes are strictly correlated to the intracellular cholesterol biosynthesis pathway. The transcription of the LDLR and the genes that are required for cholesterol and fatty acid synthesis are controlled by membrane-bound transcription factors called

Objectives

Methods

Results

Conclusion