Unveiling a New Mechanism for Maintaining Cholesterol Levels in Cell Membranes

Program-Specific Researcher (Ueda Group)

Fumihiko Ogasawara

Cholesterol is an essential lipid for human cells. It is abundant in the cell membrane, which separates the inside and outside of the cell, and is necessary for protection and proper function of the cell. In this study, Fumihiko Ogasawara and Professor Kazumitsu Ueda revealed the mechanism by which two proteins that transport cholesterol maintain the appropriate cholesterol concentration in the cell membrane.

Please share with us the significance of your manuscript in terms of its research achievements, impact, or uniqueness.

The cell membrane, which separates the inside and outside of the cell, contains a large amount of cholesterol. Cholesterol plays an important role in preventing water and ions from permeating the cell membrane, and it functions as a scaffold for intracellular signal transduction. Although cholesterol is highly concentrated in the plasma membrane, the sensors that sense its concentration (SCAP/SREBP) are located on the endoplasmic reticulum (ER) membrane, which has a low cholesterol concentration, and how they sense changes in plasma membrane cholesterol concentration has long been a mystery.
In this study, we found that two proteins that transport cholesterol, ABCA1 and Aster-A, work cooperatively to maintain the cholesterol homeostasis in cells. The cell membrane is composed of two layers of phospholipids (lipid bilayer). By transporting cholesterol from the inner layer to the outer layer of the cell membrane, ABCA1 maintains a low concentration of cholesterol in the inner layer. Aster-A transfers excess cholesterol in the inner layer to the ER, allowing SCAP/SREBP to sense changes in the cholesterol concentration of the cell membrane.

Please tell us what was the most gratifying or inspiring moment for you during this research project.

It was when I was first able to observe the coordinated movement of ABCA1 and Aster-A under the microscope. This research was motivated by a presentation I heard at an academic conference that revealed the function of Aster-A for the first time. I thought about it in conjunction with the paper on ABCA1 that I was writing at the time, and discussed it with Professor Ueda on the spot. The first results were obtained about two months later. At the time, the Aster-A paper had only just been published, and I remember how happy I was to have been able to give shape to my imagination by making use of fresh information.

Please tell us about the biggest challenge or problem you experienced while conducting your research. How did you overcome it?

We had the most difficulty in proving the movement of cholesterol within the cell. Cholesterol is a difficult lipid to label, different labeling methods show different results, and its distribution and movement is still being discussed. We tried to visualize cholesterol by multiple methods and to induce only the targeted phenomenon as much as possible, for example, by using drugs to quickly switch the activity of ABCA1 on and off. I believe that our careful and sincere approach in setting up the experimental conditions led to this paper.

Would you consider this work to be a turning point in your overall research direction? If so, how has your research direction changed as a result of this work?

The theory that ABCA1 creates asymmetric cholesterol distribution between the bilayers of the cell membrane is still new in the long history of cholesterol research, and there are many skeptical voices. I learned that persistent research is necessary to overturn the "common sense" as described in textbooks, and that it is a different degree of difficulty from making new discoveries. I hope to continue my research always unbound by preconceptions.

Please describe the current situation of your career. What is your current position? How has the knowledge and experience gained at iCeMS influenced your career?

I am still working as a researcher in the Ueda Group. iCeMS has state-of-the-art equipment and support. I was also able to use the super-resolution microscope for this research, which allowed me to obtain clear data. I hope to make the most of the experience gained in such a well-endowed research environment and bring it forward to my future career.

Paper information

ABCA1 and cholesterol transfer protein Aster-A promote an asymmetric cholesterol distribution in the plasma membrane

Fumihiko Ogasawara and Kazumitsu Ueda

Journal of Biological Chemistry

Published: December 2022

DOI: 10.1016/j.jbc.2022.102702