Impact of micelle characteristics on cholesterol absorption and ezetimibe inhibition: Insights from Niemann-Pick C1-like 1 binding and molecular structure

Abstract

Yamanashi et al., conducted a study on the absorption of cholesterol and β-sitosterol, as well as the inhibitory effect of ezetimibe (EZE). They used CaCo-2 cells to simulate the intestines and investigated how different mixed micelles, acting as carriers, were absorbed into these cells through the Niemann-Pick C1-like 1 (NPC1L1) protein. The study focused on the impact of micelle shape, size, and zeta potential on absorption and the inhibitory effect of EZE. I utilized small-angle X-ray scattering and a zeta potential measuring device to measure these characteristics. The findings revealed a two-step mechanism: NPC1L1 selectively bound micelles based on their shape and size, and once bound, the absorption was regulated by the molecular structure of the micelle components. EZE's inhibitory effect changed with micelle composition, influencing micelle size and shape. EZE initially acted on the micelle’s shape and size, and then NPC1L1 selectively bound micelles based on their shape and size, allowing EZE to directly inhibit absorption by interacting with NPC1L1. This groundbreaking discovery challenges existing concepts and holds significant implications for researchers in drug development, as well as physicians and pharmacists.

Keywords:

• Micelle properties
• cholesterol uptake
• ezetimibe inhibitory effect
• Niemann-Pick C1-like 1 interaction
• intestinal cell model
• molecular structure impact

Acknowledgements

The author extends gratitude to the Photon Factory Program Advisory Committee of the High Energy Accelerator Research Organization for granting access to the SAXS equipment at the BL-6A and BL-10C beamlines (Photon Factory, High Energy Accelerator Research Organization, Tsukuba, Ibaraki, Japan). We also appreciate their generous assistance with travel and accommodation expenses under grant numbers 2012G528, 2014G511, 2016G002, 2019G010, 2021G005, and 2023G534. Additionally, the author acknowledges the Japan Research Reactor-3 General User Program Advisory Committee of the Institute for Solid State Physics, the University of Tokyo, for providing access to the SANS equipment at the SANS-U beamline (Japan Research Reactor-3, Tokai, Ibaraki, Japan) [grant nos. 22918 and 01481]. The invaluable opportunities to perform SAXS and SANS measurements were instrumental in the completion of this article.

Disclosure Statement

No potential conflict of interest was reported by the author(s).

Data availability Statement

No specific dataset was used in the preparation of this manuscript.

Data deposition

The foundational data supporting this research has not been shared or made publicly available.

Additional information

Funding

We extend our heartfelt appreciation to the support provided by Photon Factory, High Energy Accelerator Research Organization, Tsukuba, Ibaraki, Japan, which generously covered the travel and accommodation expenses associated with this study [grant nos. 2012G528, 2014G511, 2016G002, 2019G010, 2021G005, and 2023G534]. This research was also made possible through the financial assistance of Japan Society for the Promotion of Science KAKENHI [grant no. 19K20166].