The importance of cholesterol to healthy cell functioning

This study was published in Nature Communications 2012 Dec 4;3:1249

Study title and authors:
Cholesterol modulates cell signaling and protein networking by specifically interacting with PDZ domain-containing scaffold proteins.

Sheng R, Chen Y, Yung Gee H, Stec E, Melowic HR, Blatner NR, Tun MP, Kim Y, Källberg M, Fujiwara TK, Hye Hong J, Pyo Kim K, Lu H, Kusumi A, Goo Lee M, Cho W.
Department of Chemistry, University of Illinois at Chicago, Chicago, Illinois 60607, USA.

This study can be accessed at: http://www.ncbi.nlm.nih.gov/pubmed/23212378

Wonhwa Cho, professor of chemistry at the University of Illinois at Chicago and investigator on the study notes that inside the thin membrane of a cell, cholesterol is at high levels (30 to 40 percent) which suggests that it plays an important role in cellular processes.

Scaffolding proteins play an important role in cell signaling. A scaffold protein uses its physical structure to bring together other proteins so they can pass signals to each other. They have protein binding sites that offer the signaling proteins a place to latch onto.

The authors of the study found:
(a) Cholesterol binds to a region on the scaffold protein NHERF/EBP50 where one of its signaling partners also binds.
(b) Disruption of the cholesterol binding to that site stopped the signaling partner from activating.
(c) At least seven more scaffold proteins also bind cholesterol and have cholesterol-binding sites.

This shows the influential role cholesterol may play in cell signaling through direct interactions with scaffold proteins.

This suggests this way of interacting with cholesterol could be used by many proteins inside cells and highlights the importance of cholesterol to healthy cell functioning.

Cholesterol is essential for renewal of cells and wound healing

This study was published in Experimental Cell Research Volume 300, Issue 1, 15 October 2004, Pages 109-120

Study title and authors:
Cholesterol is essential for mitosis progression and its deficiency induces polyploid cell formation
Carlos Fernández, María del Val T. Lobo, c, Diego Gómez-Coronado and Miguel A. Lasunción, d,
Servicio de Bioquímica-Investigación, Hospital Ramón y Cajal, Madrid, Spain

This paper can be accessed at: http://www.ncbi.nlm.nih.gov/pubmed/15383319

Fernández notes that cholesterol is an essential component of cell membranes.

Mitosis is a process of cell division which results in the production of two daughter cells from a single parent cell. The daughter cells are identical to one another and to the original parent cell. Mitosis plays a role in cell replacement and wound healing. Cytokinesis is the final stage of mitosis where a single parent cell forms the two new cells.

The aim of the study was to determine the role of cholesterol in mitosis. For this human cells were incubated in a cholesterol free medium and the results observed were:

(a) Prolonged cholesterol starvation inhibitied cytokinesis and caused the formation of polyploid cells, which were multinucleated (cells which have more than one nucleus per cell and are implicated in tumour formation) and had other abnormalities.
(b) Supplementing with cholesterol completely abolished these adverse effects, demonstrating they were specifically due to cholesterol deficiency.

Polyploid cells are implicated in cancer, Alzheimer's disease and ataxia telangiectasia (Ataxia-telangiectasia is rare childhood disease that affects the brain and other parts of the body such as uncoordinated movements and retarded mental ability)

Fernández concluded: "Cholesterol is essential for mitosis completion and that, in the absence of cholesterol, the cells fail to undergo cytokinesis... generating polyploid cells".

Cholesterol's Importance to the Cell Membrane

Cholesterol's Importance to the Cell Membrane
July, 2005 by Chris Masterjohn

Cholesterol is Abundant in Cell Membranes

Cholesterol is found in every cell of your body. It is especially abundant in the membranes of these cells, where it helps maintain the integrity of these membranes, and plays a role in facilitating cell signaling-- meaning the ability of your cells to communicate with each other so you function as a human, rather than a pile of cells.

Molecule for molecule, cholesterol can make up nearly half of the cell membrane.1 Since it is smaller and weighs less than other molecules in the cell membrane, it makes up a lesser proportion of the cell membrane's mass, usually roughly 20 percent.2

Cholesterol is also present in membranes of organelles inside the cells, although it usually makes up a smaller proportion of the membrane. For example, the mitochondrion, the so-called "power-house" of the cell, contains only three percent cholesterol by mass, and the endoplasmic reticulum, which is involved in making and modifying proteins, is six percent cholesterol by mass. 3

Cholesterol Maintains the Integrity of the Cell Membrane

Surrounding each of our cells is a membrane called the plasma membrane. The plasma membrane is a continuous double-layer of phospholipids, interweaved with cholesterol and proteins. Phospholipids are composed of two fatty acids attached to a phosphate compound as a head.

The phosphate head is water-soluble, also called "hydrophilic" (water-loving), and the fatty-acids are water-insoluble, or "hydrophobic" (water-fearing). Since outside the cell is a water-containing, or aqueous, environment, and inside the cell is also aqueous, the phosphate heads of the phospholipids face both the cell's inside and the environment outside the cell, while the fatty acids face the inside of the membrane.

The membrane is fluid, and the molecules are always moving. It has about the same consistency as olive oil. Cholesterol is an amphipathic molecule, meaning, like phospholipids, it contains a hydrophilic and a hydrophobic portion. Cholesterol's hydroxyl (OH) group aligns with the phosphate heads of the phospholipids. The remaining portion of it tucks into the fatty acid portion of the membrane.

Because of the way cholesterol is shaped, part of the steroid ring (the four hydrocarbon rings in between the hydroxyl group and the hydrocarbon "tail") is closely attracted to part of the fatty acid chain on the nearest phospholipid. This helps slightly immobilize the outer surface of the membrane and make it less soluble to very small water-soluble molecules that could otherwise pass through more easily.4

Without cholesterol, cell membranes would be too fluid, not firm enough, and too permeable to some molecules. In other words, it keeps the membrane from turning to mush.

Cholesterol Helps Maintain the Fluidity of Cell Membranes

While cholesterol adds firmness and integrity to the plasma membrane and prevents it from becoming overly fluid, it also helps maintain its fluidity.

At the high concentrations it is found in our cell's plasma membranes (close to 50 percent, molecule for molecule) cholesterol helps separate the phospholipids so that the fatty acid chains can't come together and cyrstallize.5

Therefore, cholesterol helps prevent extremes-- whether too fluid, or too firm-- in the consistency of the cell membrane.

Cholesterol Helps Secure Important Proteins in the Membrane

The plasma membrane contains many proteins that perform important functions like channeling or pumping substances into and out of the cell, attaching to other cells, forming borders to keep other proteins in one specific part of the cell, communicating with nearby cells, or responding to endocrine hormones from far-away cells.

Because certain proteins' size or shape requires a thicker phospholipid bed to sit in, and because certain proteins need to stick together to function properly, the fluidity of the cell membrane, where the molecules are constantly moving randomly, could pose a problem.

Fortunately, the plasma membrane contains many lipid rafts where proteins are secured. A lipid raft contains high concentrations of cholesterol and sphingolipids-- a type of phospholipid-- containing longer and more saturated fatty acid tails.

Because the fatty acids are longer and more saturated (straighter), they aggregate more, which cholesterol also helps. That part of the membrane is also thicker, making it ideal for accommodating certain proteins.6

Since the fatty acids in lipid rafts are longer, the phospholipids also move in sync with the phospholipids on the other side of the membrane.

In the rest of the membrane, the phospholipids on one side of the membrane move independently of those on the other.7

By stabilizing certain proteins together in lipid rafts, cholesterol is important to helping these proteins maintain their function.

This could range from forming blood clots or thinning blood, to allowing sugar into your cells, to burning fat, to regulating calcium in your blood, and literally includes, in some way, most of the functions in your body, although which proteins exist in lipid rafts and which do not is still being researched.

It is the proteins, after all, by which cells communicate with one another. If cells didn't communicate with one another, you and I would be a large pile of unrelated cells rather than the individuals that we are.

References

1. Alberts, et al., Molecular Biology of the Cell: Fourth Edition, New York: Garland Science, 2002, p. 588.
2. ibid, 589F.
3. ibid, 589F.
4. ibid, 588.
5. ibid, 588.
6. ibid, 589-590.
7. ibid, 590.

This article can be accessed at: http://www.cholesterol-and-health.com/Cholesterol-Cell-Membrane.html

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