Docosahexaenoic Acid Attenuates Cardiovascular Risk Factors via a Decline in Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) Plasma Levels

Abstract

Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a circulating protein that regulates cholesterol metabolism by promoting LDL receptor degradation in the liver and has recently been proposed as a therapeutic target in the management of hyperlipidaemia. We investigated the impact of dietary fat on the metabolism of sterols and on plasma PCSK9 concentrations to explore likely clinical usefulness. In a post hoc analysis of a double-blind randomised crossover controlled feeding trial, the Canola Oil Multicenter Intervention Trial (COMIT), volunteers (n = 54) with at least one condition related to metabolic syndrome consumed diets with one of the following treatment oils in beverages: (1) conventional canola oil (Canola); (2) canola oil rich in docosahexanoic acid (DHA) (CanolaDHA); and (3) high-oleic acid canola oil (CanolaOleic). The enrichment in oleic acid resulted in lower plasma cholesterol concentration compared with diets enriched in DHA. Contrarily, DHA-enriched oil significantly decreased plasma PCSK9 and triacylglycerols levels, but increased circulating levels of sterols. The variations in lathosterol, sitosterol, and campesterol indicate that plasma PCSK9 levels are sensitive to changes in cholesterol synthesis and/or absorption. There was a significant correlation between plasma PCSK9 levels and plasma triacylglicerol and apolipoprotein B levels, which was not affected by dietary fat. Therefore, our results suggest that the impact of dietary fats should not be discarded as complementary treatment in the management of patients with hyperlipidaemia. These findings should be considered in the analysis of ongoing studies and may represent a cautionary note in the treatment of patients with cardiovascular risk.

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Fig. 1

Abbreviations

ADH:

Autosomal dominant hypercholesterolaemia

Apo:

Apoprotein

Canola:

Conventional canola oil

CanolaDHA:

Canola oil rich in DHA

CanolaOleic:

High-oleic acid canola oil

CVD:

Cardiovascular disease

DHA:

Docosahexanoic acid

FID:

Flame ionization detector

HMG-CoA:

3-hydroxy-3-methylglutaryl coenzyme A

LDL:

Low-density lipoprotein

LDLR:

LDL receptor

MUFA:

Monounsaturated fatty acids

PCSK9:

Proprotein convertase subtilisin/kexin type 9

PPARγ:

Peroxisome proliferator-activated receptor γ

PUFA:

Polyunsaturated fatty acids

SREBP:

Sterol response element-binding proteins

TAG:

Triacylglycerols

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Acknowledgments

We gratefully acknowledge Khatima Khalloufi and Mohammad Abdullah from the Richardson Centre for Functional Foods and Nutraceuticals for her technical laboratory support and his help with the ELISA tests, respectively. We would like to express our gratitude to Jorge Joven, Director of Laboratoris Clínics i de la Unitat de Recerca Biomèdica (URB-CRB), for his kind advice and suggestions regarding the manuscript organisation. The authors are also grateful to the Spanish Ministry of Economy and Competitiveness (MINECO) for a FPU fellowship AP2010-1551 (C. Rodríguez-Pérez), a “Personal técnico de apoyo” Grant PTA2012-6956-E (R. Quirantes-Piné) and to CEIBiotic’s predoctoral mobility Grant (C. Rodríguez-Pérez).

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Correspondence to Antonio Segura-Carretero.

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Financial Support

Supported by Grants from Canola Council of Canada, Flax Council of Canada, Agriculture and Agri-Food Canada, Dow AgroSciences and Western Grains Research Foundation and Canada Research Chairs Program collectively provided funding for this trial through the Growing Forward program of Agriculture and Agri-Food Canada. Also supported by NIH Grant HL 49373 and National Center for Advancing Translational Sciences, National Institutes of Health, through Grant UL1TR000127. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.

Conflict of interest

Peter Jones reported receiving grants from Advanced Foods and Materials Network (AFMNet), Danone, Enzymotec, Unilever, the Canadian Institutes of Health Research (CIHR), and Canada Research Chair Endowment (CRCE) of the Federal Government of Canada. Dr. Jones also serves as President of Nutritional Fundamentals for Health Inc., which markets plant sterols among other nutraceuticals.

The other authors did not report any conflicts of financial interest.

Authorship

PJJ is responsible for the integrity and the accuracy of the data and had full access to the complete data set in the study. Study concept and design: PJJ, VRR, and SP. Acquisition of data: PJJ, VRR, and SP, Analysis and interpretation of data: CRP, AS, PJJ, VRR, and SP. Drafting of the manuscript CRP, AS, PJJ, VRR and SP. Critical revision of the manuscript for important intellectual content and final approval of the manuscript: CRP, RQP, ASC, PJJ, VRR, and SP. Obtained funding: PJJ. Study supervision: PJJ, VRR, and SP. All authors reviewed the manuscript. All authors read and approved the final manuscript.

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Rodríguez-Pérez, C., Ramprasath, V.R., Pu, S. et al. Docosahexaenoic Acid Attenuates Cardiovascular Risk Factors via a Decline in Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) Plasma Levels. Lipids 51, 75–83 (2016). https://doi.org/10.1007/s11745-015-4099-4

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Keywords

  • PCSK9
  • Fatty acids
  • Docosahexaenoic acid
  • Sterols
  • Hyperlipidaemia