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Inhibition of Niemann-Pick C1-Like 1 by Ezetimibe Reduces Dietary 5β,6β-Epoxycholesterol Absorption in Rats

  • Bungo Shirouchi
  • Yumiko Furukawa
  • Yuri Nakamura
  • Asuka Kawauchi
  • Katsumi Imaizumi
  • Hirosuke Oku
  • Masao SatoEmail author
ORIGINAL ARTICLE

Abstract

Purpose

Oxycholesterols (OCs) are produced from cholesterol by oxidation of the steroidal backbone and side-chain. OCs are present in blood and evidence suggests their involvement in disease development and progression. However, limited information is available regarding the absorption mechanisms and relative absorption rates of dietary OCs. Although ezetimibe is known to inhibit intestinal cholesterol absorption via Niemann-Pick C1-Like 1 (NPC1L1), whether it also inhibits dietary OC absorption is unclear.

Methods

We investigated the effects of ezetimibe on OC absorption in rats fed an OC-rich diet containing 10 different OCs. We collected lymphatic fluid using permanent cannulation of the thoracic duct and quantified OC levels.

Results

Ezetimibe treatment significantly reduced the apparent absorption of 5β,6β-epoxycholesterol (5,6β-epoxy) and its levels in the proximal intestinal mucosa in OC-fed rats. Using in silico analyses, the binding energy of NPC1L1 N-terminal domain (NPC1L1-NTD) and 5,6β-epoxy was found to be similar to that of NPC1L1-NTD and cholesterol, suggesting that polar uncharged amino acids located in the steroidal part of 5,6β-epoxy were involved.

Conclusion

Our results indicate that ezetimibe-mediated inhibition of dietary OC absorption varies depending on the specific OC, and only the absorption of 5,6β-epoxy is significantly reduced.

Keywords

Ezetimibe Dietary oxycholesterols Intestinal absorption Lymphatic lipid transport Permanent thoracic lymph duct cannulation 

Abbreviations

19-OH

19-hydroxycholesterol

7α-OH

7α-hydroxycholesterol

7β-OH

7β-hydroxycholesterol

25-OH

25-hydroxycholesterol

5α-OH-6-keto

5α-hydroxy-6-ketocholestanol

6-keto

6-ketocholestanol

7-keto

7-ketocholesterol

5,6α-epoxy

5α6α-epoxycholesterol

5,6β-epoxy

5β6β-epoxycholesterol

α-triol

α-cholestanetriol

β-triol

β-cholestanetriol

Niemann-Pick C1-Like 1

NPC1L1

NTD

N-terminal domain

OC

oxycholesterol

Notes

Acknowledgments

The authors thank Editage (www.editage.jp) for English language editing.

Author Contributions

B.S. wrote the manuscript. B.S., Y.F., Y. N., A.K., and H.O. participated in the experimental work and collected and analyzed data. B.S., K.I., and M.S. contributed to the study design, supervised the study, and commented on the manuscript.

Funding Information

This study was supported by JSPS KAKENHI (Grant Number 23780138 (to B.S.) and 25870507 (to B.S.)), Bayer Yakuhin, Ltd. (Osaka, Japan) (to M.S.), and the Collaborative Research of Tropical Biosphere Research Center, University of the Ryukyus (Okinawa, Japan) (to B.S.). The cost of English language editing was supported in part by Kyushu University Research Activity Support Program “English/Japanese Proofreading Expenses Support” (to B.S.).

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflict of interest.

Ethical Approval

The handling and euthanasia of all animals were carried out in accordance with nationally prescribed guidelines, and ethical approval for the studies was granted by the Animal Care and Use Committee of Kyushu University. The authorization number was A24-034-2. This article does not contain any studies with human participants performed by any of the authors.

Informed Consent

Informed consent is not applicable in this article.

Consent for Publication

All authors have approved the submission for publication of this study.

Supplementary material

10557_2019_6854_MOESM1_ESM.docx (122 kb)
ESM 1 (DOCX 122 kb)

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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Laboratory of Nutrition Chemistry, Department of Bioscience and Biotechnology, Faculty of Agriculture, Graduate SchoolKyushu UniversityFukuokaJapan
  2. 2.Tropical Biosphere Research CenterUniversity of the RyukyusNakagami-gunJapan

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