Friday, September 09, 2005

Cholesterol 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 also reduces the permeability of the plasma memebrane to proton and sodium ions (Haines 2001). 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. 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. Recently, cholesterol has also been implicated in cell signalling processes, where it has been suggested that it forms lipid rafts in the plasma membrane.

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. (In contrast, 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 to believe that lower total cholesterol levels tend to correlate with lower atherosclerosis event rates. Due to this reason, cholesterol has become a very large focus for scientific researchers trying to determine the proper amount of cholesterol needed in a healthy diet.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. In contrast, however, 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 utilizing HMG-CoA reductase inhibitors or statins, have repeatedly 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; However, no statistically significant mortality benefit has been derived to date by lowering cholesterol using medications in asymptomatic people, i.e., no heart disease, no history of heart attack, etc.

Some of the better recent randomized human outcome trials studying patients with coronary artery disease or its risk equivalents include the Heart Protection Study (HPS), the PROVE IT trial, and the TNT trial. In addition, there are trials that have looked at the effect of lowering LDL as well as raising HDL and atheroma burden using intravascular ultrasound. Small trials have shown prevention of progression of coronary artery disease and possibly a slight reduction in atheroma burden with successful treatment of an abnormal lipid profile.

The American Heart Association 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 (2.6 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.

Patients 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 that 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 that offer more-sophisticated analysis using different methodologies. As outlined above, the real key is cholesterol transport, which is determined by both the proteins that form the lipoprotein particles and the proteins on cell surfaces with which they interact.
Based on Wikipedia


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