TY - JOUR
T1 - Inhibition of Niemann-Pick C1-Like 1 by Ezetimibe Reduces Dietary 5β,6β-Epoxycholesterol Absorption in Rats
AU - Shirouchi, Bungo
AU - Furukawa, Yumiko
AU - Nakamura, Yuri
AU - Kawauchi, Asuka
AU - Imaizumi, Katsumi
AU - Oku, Hirosuke
AU - Sato, Masao
N1 - Funding Information:
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 BEnglish/Japanese Proofreading Expenses Support^ (to B.S.).
Publisher Copyright:
© 2019, Springer Science+Business Media, LLC, part of Springer Nature.
PY - 2019/2/15
Y1 - 2019/2/15
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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U2 - 10.1007/s10557-019-06854-4
DO - 10.1007/s10557-019-06854-4
M3 - Article
C2 - 30671747
AN - SCOPUS:85060548269
SN - 0920-3206
VL - 33
SP - 35
EP - 44
JO - Cardiovascular Drugs and Therapy
JF - Cardiovascular Drugs and Therapy
IS - 1
ER -