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Sesamol and sesame (Sesamum indicum) oil enhance macrophage cholesterol efflux via up-regulation of PPARγ1 and LXRα transcriptional activity in a MAPK-dependent manner

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Abstract

Purpose

Cholesterol clearance by macrophages is a vital process to eliminate excess cholesterol from the body. Internalization of modified cholesterol by macrophages triggers overexpression of peroxisome proliferator-activated receptor γ1 (PPARγ1) and liver X receptor α (LXRα), two transcription factors that are critically involved in macrophage cholesterol efflux. Recent studies demonstrate that oral administration of sesamol derivative (INV-403) and sesame oil leads to a significant attenuation of atherosclerosis in Watanabe heritable hyperlipidemic rabbits and LDLR−/− mice, respectively. However, the exact molecular mechanisms underlying such anti-atherogenic effects remain largely unrevealed.

Methods

Luciferase reporter assays were performed to assess the effects of sesamol and sesame oil on PPARγ1 and LXRα gene expression. The potential of sesamol and sesame oil to modulate cholesterol efflux was evaluated using 3H-cholesterol efflux assays.

Results

Sesamol and sesame oil treatments lead to a significant up-regulation of PPARγ1 and LXRα expression and transcriptional activity in a MAPK-dependent manner. Importantly, primary macrophages display a significantly enhanced cholesterol efflux potential upon treatment with sesamol and sesame oil, and this stimulatory effect is mediated by MAPK signaling.

Conclusions

Our findings suggest that the previously reported anti-atherogenic effects of sesamol and sesame oil could be attributed, at least in part, to enhanced PPARγ1 and LXRα expression and transcriptional activity leading to improved macrophage cholesterol efflux. Our study is novel in elucidating the molecular and cellular mechanisms underlying the protective effects of sesamol and sesame oil against atherosclerosis.

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Acknowledgments

We are thankful to Dr. Johan Auwerx (University Louis Pasteur, Strasbourg, France), Dr. Knut Steffensen (Karolinska Institute, Huddinge, Sweden), Dr. Bruce Spiegelman (Harvard Medical School, Massachusetts, USA), and Dr. David Mangelsdorf (Howard Hughes Medical Institute, Maryland, USA) for kindly providing us with pGL3-PPARγ1-luciferase, pGL3-LXRα-luciferase, pGL3-TK-PPRE-X3-luciferase, and pGL3-TK-LXRE-X3-luciferase reporter constructs, respectively. We thank Dr. Neale Ridgway (Dalhousie University, Nova Scotia, Canada) for providing us with lipoprotein-depleted FBS used in 3H-cholesterol efflux assays. This work was supported by a grant from the Canadian Institute of Health Research (CIHR) (Grant MOP-57675) to H.S. Ro and a Faculty Research Grant (FRG10-07) to A. Majdalawieh.

Conflict of interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Department of Biology, Chemistry and Environmental Sciences, College of Arts and Sciences, American University of Sharjah, P.O. Box 26666, Sharjah, United Arab Emirates

    Amin F. Majdalawieh

  2. Department of Biochemistry and Molecular Biology, Faculty of Medicine, Dalhousie University, Halifax, Nova Scotia, B3H 1X5, Canada

    Hyo-Sung Ro

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Correspondence to Amin F. Majdalawieh.

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Majdalawieh, A.F., Ro, HS. Sesamol and sesame (Sesamum indicum) oil enhance macrophage cholesterol efflux via up-regulation of PPARγ1 and LXRα transcriptional activity in a MAPK-dependent manner. Eur J Nutr 54, 691–700 (2015). https://doi.org/10.1007/s00394-014-0747-3

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