Cholesterol is a steroid lipid,
found in the cell membranes of all body tissues, and transported in the blood plasma of all animals. Most cholesterol is not dietary in origin, it is synthesized internally. It is present
in higher concentrations in tissues which either produce more or have more densely packed membranes; for example the liver, spinal cord, brain and atheroma. Cholesterol plays a central role in many
biochemical processes, but is best known for the association of cardiovascular disease with various lipoprotein cholesterol transport
patterns in the blood.
History of the name
The name originates from the Greek chole- (bile) and stereos (solid), as
researchers first identified cholesterol in solid form in gallstones.
Physiology
Synthesis
Cholesterol is primarily synthesized from acetyl CoA through the HMG-CoA reductase pathway in many cells/tissues. About 20–25% of total daily production (~1 g/day) occurs in the liver, other sites of
higher synthesis rates include the intestines, adrenal glands and reproductive
organs. For a person of about 150 pounds, typical total body content is about 35 gms (3,500 mg), typical daily internal
production is about 1000 mg and typical daily dietary intake is 200 to 300 mg. Of the 1,200 to 1,300 mg input to the intestines
(via bile production and food intake), about 50% is typically reabsorbed into the bloodstream.
Properties
Cholesterol is minimally soluble in water; it cannot dissolve and travel in the
water-based blood stream. Instead, it is transported in the blood stream by lipoproteins; protein "molecular-suitcases" which are water soluble and carry cholesterol and fats internally.
The proteins forming the surface of the given lipoprotein particle determine
from what cells cholesterol will be removed and to where it will be supplied.
The largest lipoproteins, which primarily transport fats from the intestinal
mucosa to the liver are called chylomicrons. They carry mostly triglyceride fats and cholesterol (both from food and especially internal
cholesterol secreted by the liver into the bile). In the liver, chylomicron particles
give up triglycerides and some cholesterol and are converted into low-density lipoprotein (LDL) particles which carry triglycerides and cholesterol on to other body
cells. In healthy individuals the low-density
lipoprotein (LDL) particles are large and relatively few in number. Conversely, large numbers of small low-density lipoprotein (LDL) particles are strongly
associated with promoting atheromatous disease within the arteries. (Lack of
information on low-density lipoprotein (LDL) particle
number and size is one of the major problems of conventional lipid tests.)
High-density lipoprotein (HDL) particles
transport cholesterol back to the liver for excretion, but vary considerably in their effectiveness for doing this. Having large
numbers of large HDL particles correlates with
better health outcomes. Conversely, having small amounts of large HDL particles is strongly associated with atheromatous disease progression within the arteries. (Note that the concentration of total HDL does not indicate the actual number of functional large
HDL particles, one of the major problems of
conventional lipid tests.)
The cholesterol molecules present in LDL cholesterol and
the cholesterol in HDL cholesterol are identical. The
difference between the two cholesterol derives from the carrier protein molecules (i.e. the lipoprotein) component.
Regulation
Biosynthesis of cholesterol is directly regulated by the cholesterol levels present, though the homeostatic mechanisms involved are only partly understood. A higher intake in food leads to a net
decrease in endogenous production and vice versa. The main regulatory mechanism is the sensing of intracellular cholesterol in the endoplasmic reticulum by the protein SREBP (Sterol
Regulatory Element Binding Protein 1 and 2). In the presence of cholesterol, SREBP is bound to two other proteins: SCAP
(SREBP-cleavage activating protein) and Insig-1. When cholesterol levels fall, Insig-1 dissociates from the SREBP-SCAP complex,
allowing the complex to migrate to the Golgi apparatus, where SREBP
is cleaved by S1P and S2P (site 1/2 protease), two enzymes that are activated by SCAP when cholesterol levels are low. The
cleaved SREBP then migrates to the nucleus and acts as a transcription factor to bind to the "Sterol Regulatory Element" of a number of genes to stimulate
their transcription. Amongst the genes transcribed are the LDL receptor and HMG-CoA
reductase. The former scavenges circulating LDL from the bloodstream, while HMG-CoA reductase leads to an increase of
endogenous production of cholesterol.
A large part of this mechanism was clarified by Dr Michael S. Brown and Dr Joseph L.
Goldstein in the 1970s. They received the Nobel Prize in Physiology or
Medicine for their work in 1985.
The average amount of blood cholesterol varies with age, typically rising gradually until one is about 60 years old. A study
by Ockrene et al. showed that there are seasonal variations in cholesterol levels in humans, more on average in
winter.
Function
Cholesterol is an important component of the membranes of cells, providing stability, it makes the membrane's fluidity stable over a
bigger temperature interval. The hydroxyl group on cholesterol interacts with the phosphate head of the membrane and the bulky
steroid and the hydrocarbon chain is embedded in the membrane. It is the major precursor for the synthesis of vitamin D, of the various steroid
hormones, including cortisol, cortisone, and aldosterone in the adrenal glands, and of the sex hormones progesterone, estrogen, and testosterone. The presence of cholesterol has a direct effect on the fluidity of the membrane. Further recent
research shows that cholesterol has an important role for the brain synapses as well
as in the immune system, including protecting against cancer.
Excretion
Cholesterol is excreted from the liver in bile
and reabsorbed from the intestines. Under certain circumstances, when more concentrated, as in the gallbladder, it crystallises and is the major constituent of most gallstones, although lecitin and bilirubin gallstones also occur less frequently.
See also the main article hypercholesterolemia
In conditions with elevated concentrations of LDL particles, especially small LDL
particles, cholesterol promotes atheroma plaque deposits in the walls of arteries, a condition known as atherosclerosis, which is a major contributor to coronary heart disease and other forms of cardiovascular disease. (Conversely, HDL particles have been the only identified mechanism by
which cholesterol can be removed from atheroma. Increased concentrations of large
HDL particles, not total HDL particles, correlate with lower rates of atheroma progressions, even regression.)
There is a world-wide trend that lower total cholesterol levels tend to correlate with lower atherosclerosis event rates.
However, the primary association of atherosclerosis with cholesterol has always been specifically with cholesterol transport
patterns, not total cholesterol per se. For example, total cholesterol can be low, yet made up primarily of small LDL and small
HDL particles and atheroma growth rates are high. Conversely, if LDL particle
number is low (mostly large particles) and a large percentage of the HDL particles are large (HDL is actively reverse
transporting cholesterol), then atheroma growth rates are usually low, even
negative, for any given total cholesterol concentration.
Multiple human trials using the increasingly more effective combination treatment strategies which have been developed
overtime, have repeated confirmed that changing lipoprotein transport patterns from unhealthy to healthier patterns significantly
lower cardiovascular disease event rates, even for people with cholesterol values currently considered low for adults. Some of
the better recent randomized human outcome trials include ASCOT-LLA, REVERSAL, the A to Z trial, ALLHAT-LLT, PROVE-IT, CARDS, and
the Heart Protection Study, and especially a newer research approach utilizing a synthetically produced and IV administered human
HDL, the Apo A-I Milano Trial.
The American Heart Association (http://www.americanheart.org/cholesterol/about.jsp) provides a set of guidelines for total
(fasting) blood cholesterol levels and risk for heart disease:
| Level mg/dL |
Level mmol/L |
Interpretation |
| <200 |
<5.2 |
Desirable level corresponding to lower risk for heart disease |
| 200-239 |
5.2-6.2 |
Borderline high risk |
| >240 |
>6.2 |
High risk |
However, as today's testing methods determine LDL ("bad") and HDL ("good") cholesterol separately, this simplistic view
has become somewhat outdated. The desirable LDL level is considered to be less than 100 mg/dl
(1.9 mmol/L),although a newer
target of <70 mg/dl can be considered in higher risk individuals based on some of the above mentioned trials. A ratio of total
cholesterol to HDL—another useful
measure—of far less than 5:1 is thought to be healthier. Of note, typical LDL values for children before fatty streaks begin to develop is 35 mg/dl.
Patient's should be aware that most testing methods for LDL do not actually measure LDL in their blood, much less particle
size. For cost reasons, LDL values have long been estimated using the formula: Total-cholesterol − total-HDL − 20% of
the triglyceride value = estimated LDL.
Increasing clinical evidence has strongly supported the greater predictive value of more sophisticated testing which directly
measures both LDL and HDL particle concentrations and size as opposed to the more
usual estimates/measures of the total cholesterol carried within LDL particles or the total HDL concentration. There are three
commercial labs in the United States which offer more sophisticated analysis using different methodologies. As outlined above,
the real key is cholesterol transport which is determined by both the proteins which form the lipoprotein particles and the proteins on cell surfaces with which they interact.
Cholesteric liquid crystals
Some cholesterol derivatives, (among others simple cholesteric lipids) are known to generate liquid crystalline phase called "cholesteric". The cholesteric phase is in fact a chiral nematic phase and changes colour when
its temperature changes. Therefore cholesterol derivatives are commonly used as temperature sensitive dyes, in liquid crystal thermometers, and in temperature sensitive
paints.
Sources
- Anderson RG. Joe Goldstein and Mike Brown: from cholesterol homeostasis to new paradigms in membrane biology. Trends Cell
Biol 2003:13:534-9. PMID
14507481.
- Ockene IS, Chiriboga DE, Stanek EJ 3rd, Harmatz MG, Nicolosi R, Saperia G, Well AD, Freedson P, Merriam PA, Reed G, Ma Y,
Matthews CE, Hebert JR. Seasonal variation in serum cholesterol levels: treatment implications and possible mechanisms.
Arch Intern Med 2004;164:863-70. PMID
15111372.
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