Although it has a bad reputation for posing a health concern when blood levels of cholesterol are too high, cholesterol is an essential component of the membrane that encircles every human cell. The key to optimal health is having the appropriate amount of cholesterol in the right places. Cholesterol homeostasis refers to maintaining healthy levels. New details on how cells keep cholesterol homeostasis within the cell membrane have been discovered by researchers at Kyoto University in Japan’s Institute for Integrated Cell-Material Science (iCeMS). The Journal of Biological Chemistry publishes the findings.
The density of cholesterol molecules within the cell membrane regulates the fluidity, thickness, and flexibility of the membrane.
These features are essential for the membrane to function as a selective semi-permeable barrier, allowing for precise regulation of the chemicals that can enter and exit cells.
“Disturbances in cholesterol homeostasis can lead to some serious diseases, but it has been unclear how cells detect and respond to changes in cholesterol levels in the cell membrane,” says iCeMS cellular biochemist Kazumitsu Ueda.
A crucial function of two proteins in preserving an optimal distribution of cholesterol inside cells and their membranes has recently been identified by Ueda and his colleague Fumihiko Ogasawara. ATP-binding cassette A1 (ABCA1), the first protein, transports cholesterol within the membrane. A lipid bilayer, consisting of inner and outer layers of fatty molecules (phospholipids, cholesterol, and glycolipids) that are positioned in opposition to one another, makes up the cell membrane.
The ABCA1 protein regulates the movement of cholesterol molecules from the inner layer to the outer layer, which is a significant new discovery revealed in the current study. This procedure is known as “cholesterol flipping” by the researchers. Their earlier research focused on how this protein helps high-density lipoprotein (HDL), sometimes known as good cholesterol, transport cholesterol through the circulation.
Aster-A, a protein that transfers cholesterol, was also discovered by Ueda and Ogasawara to work in conjunction with ABCA1 to maintain the essential asymmetric distribution of cholesterol, with more cholesterol in the outer layer of the cell membrane than the interior. The endoplasmic reticulum of the cell contains Aster-A, which is inside the cell.
Aster-A creates a bridge that transports cholesterol from the cell membrane to the endoplasmic reticulum when the amount of cholesterol in the inner layer of the cell membrane rises.
The researchers explain how cholesterol may act as a signalling agent in the membrane due to its uneven distribution, with the degree of asymmetry determining how it affects other cellular functions. They contend that this explains why flaws in ABCA1’s normal operation can result in improper molecular signalling, which can cause cancer and autoimmune disorders.
“The progress we have made needs to be built on to better understand all the implications of these cholesterol homeostasis processes in both health and disease,” Ueda concludes. He hopes this may eventually open new avenues to treating diseases linked to cholesterol imbalance.