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 Sato

研究成果: ジャーナルへの寄稿記事

抄録

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.

元の言語英語
ページ(範囲)35-44
ページ数10
ジャーナルCardiovascular Drugs and Therapy
33
発行部数1
DOI
出版物ステータス出版済み - 2 15 2019

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Cholesterol
Thoracic Duct
Intestinal Absorption
Intestinal Mucosa
5,6-epoxycholesterol
Ezetimibe
Catheterization
Computer Simulation
Disease Progression
Diet
Amino Acids
Therapeutics

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Cardiology and Cardiovascular Medicine
  • Pharmacology (medical)

これを引用

Inhibition of Niemann-Pick C1-Like 1 by Ezetimibe Reduces Dietary 5β,6β-Epoxycholesterol Absorption in Rats. / Shirouchi, Bungo; Furukawa, Yumiko; Nakamura, Yuri; Kawauchi, Asuka; Imaizumi, Katsumi; Oku, Hirosuke; Sato, Masao.

:: Cardiovascular Drugs and Therapy, 巻 33, 番号 1, 15.02.2019, p. 35-44.

研究成果: ジャーナルへの寄稿記事

Shirouchi, Bungo ; Furukawa, Yumiko ; Nakamura, Yuri ; Kawauchi, Asuka ; Imaizumi, Katsumi ; Oku, Hirosuke ; Sato, Masao. / Inhibition of Niemann-Pick C1-Like 1 by Ezetimibe Reduces Dietary 5β,6β-Epoxycholesterol Absorption in Rats. :: Cardiovascular Drugs and Therapy. 2019 ; 巻 33, 番号 1. pp. 35-44.
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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.",
author = "Bungo Shirouchi and Yumiko Furukawa and Yuri Nakamura and Asuka Kawauchi and Katsumi Imaizumi and Hirosuke Oku and Masao Sato",
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AU - Nakamura, Yuri

AU - Kawauchi, Asuka

AU - Imaizumi, Katsumi

AU - Oku, Hirosuke

AU - Sato, Masao

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N2 - 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.

AB - 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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