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

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.