Lipid bilayers in mammalian membranes can have a more asymmetric composition than previously thought, new research shows. This lipid abundance asymmetry is enabled by the unique properties of cholesterol and endows biomembranes with specific properties and physiological roles.

“This work challenges a major assumption of cell biology by showing that the plasma membrane, the flexible bilayer that surrounds the cell, can have drastically different phospholipid* abundances between its two leaflets”, says Milka Doktorova, first author of the study.

*phospholipids are the main component of the cell membrane. They have heads that like water and tails that do not, and line up in two layers with their heads pointing out and their tails pointing in.

Important barrier

For each of the trillions of cells in our body, the crucial job of separating the inside of the cell from the outside is performed by extremely thin membranes. These membranes are made of fats called lipids, many of which are the same fats that we consume in our diets. Despite being extremely thin, cell membranes are made of two distinct layers – often called leaflets. While the two leaflets of man-made membranes* are almost always the same, living membranes are almost always asymmetric, in that they have very different lipids in the two leaflets.

“Our cells use a tremendous amount of energy to maintain this arrangement, which is crucial for cell life and communication”, says Milka Doktorova.

*man-made membranes are synthetic membranes, i.e. lipid membranes that we can prepare in the lab and study with a variety of techniques. They are often called ‘model membranes’ and are simpler versions of the more complex cell membranes. Most of what we know about how different types of lipids affect the properties of the membrane comes from studies with model membranes. But these model membranes almost always have two leaflets with identical lipid compositions and properties which is in drastic contrast to actual cell membranes which are asymmetric.

Different numbers of lipids

While it has been known for 50 years that the two cell membrane leaflets are made of different types of lipids, it has been assumed by researchers that these two leaflets have roughly the same numbers of lipids.

“The assumption is obvious: imagine a sandwich where one piece of bread is much bigger than the other… every bite would be a mess!”, says Milka Doktorova.

But the Levental Laboratory of Membrane Biology in Virginia, USA, and the Doktorova Cell Membrane Biophysics Lab at Stockholm University, in Sweden, discovered that this assumption is – in their own words – “generally invalid and for mammalian membranes, dramatically incorrect”. It turns out that two aspects allow very different lipid numbers in our membranes. The leaflets can stretch and squeeze to fit together, according to the researchers “more like spongy bun than a crispy cracker”, and cholesterol, the most abundant lipid component of our membranes, can act as a buffer and redistribute between the two leaflets to maintain robust barriers in spite of chemical and physical imbalances.

New understanding of cell membranes

Not only does this finding contradict old assumption underlying current understanding of cell membranes, but it also provides key insights about how such membranes work and what their asymmetry might be for. The group explored several of these implications, finding that membrane asymmetry is a critical controller of the mechanisms by which cells decide whether to deposit cholesterol into fat storage depots.

“Such depots – called fat droplets - are crucial for health and disease, connecting fundamental cell biophysics to clinical relevance” says Milka Doktorova.

Find the publication in Cell Press "Cell membranes sustain phospholipid imbalance via cholesterol asymmetry": https://www.cell.com/cell/fulltext/S0092-8674(25)00270-3