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 the principal sterol of all animals, distributed in body tissues, especially the brain and spinal cord, and in animal fats and oils.[3][4]

Cholesterol is biosynthesized by all animal cells[5] 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.[6] It is absent among prokaryotes (bacteria and archaea), although there are some exceptions, such as Mycoplasma, which require cholesterol for growth.[7] Cholesterol also serves as a precursor for the biosynthesis of steroid hormones, bile acid,[8] and vitamin D.

Elevated levels of cholesterol in the blood, especially when bound to low-density lipoprotein (LDL, often referred to as "bad cholesterol"), may increase the risk of cardiovascular disease.[9]

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".[10][11]

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.[12] 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.[13]

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.[14] A human male weighing 68 kg (150 lb) normally synthesizes about 1 gram (1,000 mg) of cholesterol per day, and his body contains about 35 g, mostly contained within the cell membranes.[citation needed]

Typical daily cholesterol dietary intake for a man in the United States is 307 mg.[15] 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.[16] 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.[17] 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 (which transport all fats in the water outside cells), the concentrations increase.[18]

Plants make cholesterol in very small amounts.[19] In larger quantities they produce phytosterols, chemically similar substances that compete with cholesterol for reabsorption in the intestinal tract, thus potentially reducing cholesterol reabsorption.[20] 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 ≈200‍–‍300 mg/day depending on eating habits.[21] Specially designed vegetarian experimental diets have been produced yielding upwards of 700 mg/day.[22]

Function

Cholesterol is present in varying degrees in all animal cell membranes but is absent in prokaryotes.[23] 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[24] and maintains membrane integrity so that animal cells do not need to build cell walls (like plants and most bacteria). The membrane remains stable and durable without being rigid, allowing animal cells to change shape and animals to move.[citation needed]

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.[25] In this structural role, cholesterol also reduces the permeability of the plasma membrane to neutral solutes,[26] hydrogen ions, and sodium ions.[27]

Cholesterol regulates the biological process of substrate presentation and the enzymes that use substrate presentation as a mechanism of their activation. Phospholipase D2 (PLD2) is a well-defined example of an enzyme activated by substrate presentation.[28] 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 (PC) 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 (PIP2). 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.[citation needed]

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.[29] In multiple layers, cholesterol and phospholipids (both electrical insulators) 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.[30]Demyelination (loss of myelin) is believed to be part of the basis for multiple sclerosis.[31]

Cholesterol binds to and affects the gating of a number of ion channels such as the nicotinic acetylcholine receptor, GABAA receptor, and the inward-rectifier potassium channel.[32] Cholesterol activates the estrogen-related receptor alpha (ERRα) and may be the endogenous ligand for the receptor.[33][34] The constitutively active nature of the receptor may be explained by the fact that cholesterol is ubiquitous in the body.[34] 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.[33][34] On the basis of these findings, it has been suggested that the ERRα should be de-orphanized and classified as a receptor for cholesterol.[33][34]