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Cardiovascular Drugs and Therapy

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01-02-2019 | Ezetimibe | ORIGINAL ARTICLE

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

Authors: Bungo Shirouchi, Yumiko Furukawa, Yuri Nakamura, Asuka Kawauchi, Katsumi Imaizumi, Hirosuke Oku, Masao Sato

Published in: Cardiovascular Drugs and Therapy | Issue 1/2019

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.

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Title: Inhibition of Niemann-Pick C1-Like 1 by Ezetimibe Reduces Dietary 5β,6β-Epoxycholesterol Absorption in Rats
Authors: Bungo Shirouchi
Yumiko Furukawa
Yuri Nakamura
Asuka Kawauchi
Katsumi Imaizumi
Hirosuke Oku
Masao Sato
Publication date: 01-02-2019
Publisher: Springer US
Keyword: Ezetimibe
Published in: Cardiovascular Drugs and Therapy / Issue 1/2019
Print ISSN: 0920-3206
Electronic ISSN: 1573-7241
DOI: https://doi.org/10.1007/s10557-019-06854-4

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

Abstract

Purpose

Methods

Results

Conclusion

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