Study Offers New Insights into How Cells Maintain Cholesterol Homeostasis

Researchers at Kyoto University’s Institute for Integrated Cell-Material Science (iCeMS) in Japan report new insights into how cells maintain proper cholesterol balance within the cell membrane. The revelations regarding two key proteins that maintain the asymmetric distribution of cholesterol within the cell membrane could help understand and treat diseases linked to its imbalance.

Cholesterol molecules are packed inside the cell membrane at levels that control membrane fluidity, thickness and flexibility.  These characteristics are vital for making the membrane a selective semi-permeable barrier, with crucial control over what substances can travel into and out of cells.

Despite being an essential component of the membrane surrounding every human cell, cholesterol is most associated with health concerns when present in high levels in the blood. Research has shown that having the right amount of cholesterol in the right places—a state known as cholesterol homeostasis—is key to overall health.

“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.

In a paper published recently in Journal of Biological Chemistry, Ueda and colleague Fumihiko Ogasawara detail the vital role of two proteins in maintaining an appropriate distribution of cholesterol inside cells and their membranes.

The first protein, ATP-binding cassette A1 (ABCA1), translocates cholesterol within the membrane. The cell membrane is composed of a lipid bilayer, with inner and outer layers of fatty molecules—namely, phospholipids, cholesterol, and glycolipids—oriented in opposite directions. The study found that the ABCA1 protein controls the transfer of cholesterol molecules from the inner layer to the outer layer, a process the team dubbed “cholesterol flopping.” Previous work by the team had explored this protein’s role in facilitating cholesterol transfer through the bloodstream in the form of high-density lipoprotein (HDL), sometimes called good cholesterol.

Ueda and colleague Ogasawara also uncovered details of how a second protein—cholesterol transfer protein Aster-A—acts cooperatively with ABCA1 to maintain the crucial asymmetric distribution of cholesterol, with more cholesterol in the outer layer of the cell membrane than the inner. Aster-A is located inside the cell embedded in the endoplasmic reticulum. When there is an increase in the cholesterol level in the inner layer of the cell membrane, Aster-A forms a bridge transferring cholesterol from the cell membrane to the endoplasmic reticulum.

The researchers note that asymmetric distribution of cholesterol in the membrane allows it to serve a signaling function, influencing other cellular processes in ways that depend on the degree of asymmetry. They suggest that this explains why defects in the normal functioning of ABCA1 can cause faulty molecular signaling that may lead to cancer and autoimmune diseases.

“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 says. The authors hope the findings may eventually open new avenues to treating diseases linked to cholesterol imbalance.