Cholesterol

Cholesterol is the principal sterol of all animals, distributed in body tissues, especially the brain and spinal cord, and in animal fats and oils.
Cholesterol is biosynthesized by all animal cells and is an essential structural and signaling component of animal cell membranes. In vertebrates, hepatic cells typically produce the greatest amounts. In the brain, astrocytes produce cholesterol and transport it to neurons. It is absent among prokaryotes, although there are some exceptions, such as Mycoplasma, which require cholesterol for growth. Cholesterol also serves as a precursor for the biosynthesis of steroid hormones, bile acid, and vitamin D.
Elevated levels of cholesterol in the blood, especially when bound to low-density lipoprotein, may increase the risk of cardiovascular disease.
François Poulletier de la Salle first identified cholesterol in solid form in gallstones in 1769. In 1815, chemist Michel Eugène Chevreul named the compound "cholesterine".

Etymology

The word cholesterol comes from Ancient Greek chole- 'bile' and stereos 'solid', followed by the chemical suffix -ol for an alcohol.

Physiology

Cholesterol is essential for all animal life. While most cells are capable of synthesizing it, the majority of cholesterol is ingested or synthesized by hepatocytes and transported in the blood to peripheral cells. The levels of cholesterol in peripheral tissues are dictated by a balance of uptake and export. Under normal conditions, brain cholesterol is separate from peripheral cholesterol, i.e., the dietary and hepatic cholesterol do not cross the blood brain barrier. Rather, astrocytes produce and distribute cholesterol in the brain.
De novo synthesis, both in astrocytes and hepatocytes, occurs by a complex 37-step process. This begins with the mevalonate or HMG-CoA reductase pathway, the target of statin drugs, which encompasses the first 18 steps. This is followed by 19 additional steps to convert the resulting lanosterol into cholesterol. A human male weighing 68 kg normally synthesizes about 1 gram of cholesterol per day, and his body contains about 35 g, mostly contained within the cell membranes.
Typical daily cholesterol dietary intake for a man in the United States is 307 mg. Most ingested cholesterol is esterified, which causes it to be poorly absorbed by the gut. The body also compensates for absorption of ingested cholesterol by reducing its own cholesterol synthesis. For these reasons, cholesterol in food, seven to ten hours after ingestion, has little, if any effect on concentrations of cholesterol in the blood. Conversely, in rats, blood cholesterol is inversely correlated with cholesterol consumption: the more cholesterol a rat eats the lower the blood cholesterol. During the first seven hours after ingestion of cholesterol, as absorbed fats are being distributed around the body within extracellular water by the various lipoproteins, the concentrations increase.
Plants make cholesterol in very small amounts. In larger quantities they produce phytosterols, chemically similar substances that compete with cholesterol for reabsorption in the intestinal tract, thus potentially reducing cholesterol reabsorption. When intestinal lining cells absorb phytosterols, in place of cholesterol, they usually excrete the phytosterol molecules back into the GI tract, an important protective mechanism. The intake of naturally occurring phytosterols, which encompass plant sterols and stanols, ranges between ≈200300 mg/day depending on eating habits. Specially designed vegetarian experimental diets have been produced yielding upwards of 700 mg/day.

Function

Membranes

Cholesterol is present in varying degrees in all animal cell membranes but is absent in prokaryotes. It is required to build and maintain membranes and modulates membrane fluidity over the range of physiological temperatures. The hydroxyl group of each cholesterol molecule interacts with water molecules surrounding the membrane, as do the polar heads of the membrane phospholipids and sphingolipids, while the bulky steroid and the hydrocarbon chain are embedded in the membrane, alongside the nonpolar fatty-acid chain of the other lipids. Through the interaction with the phospholipid fatty-acid chains, cholesterol increases membrane packing, which both alters membrane fluidity and maintains membrane integrity so that animal cells do not need to build cell walls. The membrane remains stable and durable without being rigid, allowing animal cells to change shape and animals to move.
The structure of the tetracyclic ring of cholesterol contributes to the fluidity of the cell membrane, as the molecule is in a trans conformation, making all but the side chain of cholesterol rigid and planar. In this structural role, cholesterol also reduces the permeability of the plasma membrane to neutral solutes, hydrogen ions, and sodium ions.

Substrate presentation

Cholesterol regulates the biological process of substrate presentation and the enzymes that use substrate presentation as a mechanism of their activation. Phospholipase D2 is a well-defined example of an enzyme activated by substrate presentation. The enzyme is palmitoylated causing the enzyme to traffic to cholesterol dependent lipid domains sometimes called "lipid rafts". The substrate of phospholipase D is phosphatidylcholine which is unsaturated and is of low abundance in lipid rafts. PC localizes to the disordered region of the cell along with the polyunsaturated lipid phosphatidylinositol 4,5-bisphosphate. PLD2 has a PIP2 binding domain. When PIP2 concentration in the membrane increases, PLD2 leaves the cholesterol-dependent domains and binds to PIP2 where it then gains access to its substrate PC and commences catalysis based on substrate presentation.
File:Enzyme translocation.png|thumb|right|upright=2|class=skin-invert-image|Substrate presentation; PLD is sequestered into cholesterol-dependent lipid domains by palmitoylation. PLD also binds PIP2 domains located in the disordered region of the cell with phosphatidylcholine. When cholesterol decreases or PIP2 increases in the cell, PLD translocates to PIP2 where it is exposed to and hydrolizes PC to phosphatidic acid.

Signaling

Cholesterol is implicated in cell signaling processes, assisting in the formation of lipid rafts in the plasma membrane, which brings receptor proteins in close proximity with high concentrations of second messenger molecules. In multiple layers, cholesterol and phospholipids can facilitate speed of transmission of electrical impulses along nerve tissue. For many neuron fibers, a myelin sheath, rich in cholesterol since it is derived from compacted layers of Schwann cell or oligodendrocyte membranes, provides insulation for more efficient conduction of impulses.Demyelination is believed to be part of the basis for multiple sclerosis.
Cholesterol binds to and affects the gating of a number of ion channels such as the nicotinic acetylcholine receptor, GABA_A receptor, and the inward-rectifier potassium channel. Cholesterol activates the estrogen-related receptor alpha and may be the endogenous ligand for the receptor. The constitutively active nature of the receptor may be explained by the fact that cholesterol is ubiquitous in the body. Inhibition of ERRα signaling by reduction of cholesterol production has been identified as a key mediator of the effects of statins and bisphosphonates on bone, muscle, and macrophages. On the basis of these findings, it has been suggested that the ERRα should be de-orphanized and classified as a receptor for cholesterol.

As a chemical precursor

Within cells, cholesterol is a precursor molecule for several biochemical pathways. For example, it is the precursor molecule for the synthesis of vitamin D in the calcium metabolism and all steroid hormones, including the adrenal gland hormones cortisol and aldosterone, as well as the sex hormones progesterone, estrogens, and testosterone, and their derivatives.

Epidermis

The stratum corneum is the outermost layer of the epidermis. It is composed of terminally differentiated and enucleated corneocytes that reside within a lipid matrix, like "bricks and mortar." Together with ceramides and free fatty acids, cholesterol forms the lipid mortar, a water-impermeable barrier that prevents evaporative water loss. As a rule of thumb, the epidermal lipid matrix is composed of an equimolar mixture of ceramides, cholesterol, and free fatty acids, with smaller quantities of other lipids also present. Cholesterol sulfate reaches its highest concentration in the granular layer of the epidermis. Steroid sulfate sulfatase then decreases its concentration in the stratum corneum, the outermost layer of the epidermis. The relative abundance of cholesterol sulfate in the epidermis varies across different body sites with the heel of the foot having the lowest concentration.

Metabolism

Cholesterol is recycled in the body. The liver excretes cholesterol into biliary fluids, which are then stored in the gallbladder from where they are excreted in a non-esterified form into the digestive tract. Typically, about 50% of the excreted cholesterol is reabsorbed by the small intestine back into the bloodstream.

Biosynthesis and regulation

Biosynthesis

Almost all animal tissues synthesize cholesterol from acetyl-CoA. All animal cells manufacture cholesterol, for both membrane structure and other uses, with relative production rates varying by cell type and organ function. About 80% of total daily cholesterol production occurs in the liver and the intestines; other sites of higher synthesis rates include the brain, the adrenal glands, and the reproductive organs.
Synthesis within the body starts with the mevalonate pathway where two molecules of acetyl-CoA condense to form acetoacetyl-CoA. This is followed by a second condensation between acetyl-CoA and acetoacetyl-CoA to form 3-hydroxy-3-methylglutaryl CoA.
This molecule is then reduced to mevalonate by the enzyme HMG-CoA reductase. Production of mevalonate is the rate-limiting and irreversible step in cholesterol synthesis and is the site of action for statins.
Mevalonate is finally converted to isopentenyl pyrophosphate through two phosphorylation steps and one decarboxylation step that requires ATP.
Three molecules of isopentenyl pyrophosphate condense to form farnesyl pyrophosphate through the action of geranyl transferase.
Two molecules of farnesyl pyrophosphate then condense to form squalene by the action of squalene synthase in the endoplasmic reticulum.
Oxidosqualene cyclase then cyclizes squalene to form lanosterol.
Finally, lanosterol is converted to cholesterol via either of two pathways, the Bloch pathway, or the Kandutsch-Russell pathway. The final 19 steps to cholesterol contain NADPH and oxygen to help oxidize methyl groups for the removal of carbons, mutases to move alkene groups, and NADH to help reduce ketones.
Konrad Bloch and Feodor Lynen shared the Nobel Prize in Physiology or Medicine in 1964 for their discoveries concerning some of the mechanisms and methods of regulation of cholesterol and fatty acid metabolism.