- [Endothelial dysfunction]?
- [Cardiovascular disease, ABO blood groups and secretor status]?
Cholesterol is a sterol (a combination steroid and alcohol) and a lipid found in the cell membranes of all body tissues, and transported in the blood plasma of all animals. The name originates from the Greek chole- (bile) and stereos (solid), and the chemical suffix -ol for an alcohol, as researchers first identified cholesterol (C27H45OH) in solid form in gallstones in 1784.
Most cholesterol is not dietary in origin; it is synthesized internally. Cholesterol is present in higher concentrations in tissues which either produce more or have more densely-packed membranes, for example, the liver, spinal cord and brain, and also in 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 and high levels of cholesterol in the blood.
Often, when most doctors talk to their patients about the health concerns of cholesterol, they are referring to "bad cholesterol", or low-density lipoprotein (LDL). "Good cholesterol" is high-density lipoprotein (HDL).
Cholesterol is required to build and maintain cell membranes; it makes the membrane's fluidity - degree of viscosity - stable over bigger temperature intervals (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). Cholesterol also aids in the manufacture of bile (which helps digest fats), and is also important for the metabolism of fat soluble vitamins, including vitamins A, D, E and K. It is the major precursor for the synthesis of vitamin D, of the various steroid hormones, including cortisol 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. It also reduces the permeability of the plasma membrane to proton and sodium ions (Haines 2001).
Cholesterol is minimally soluble in water; it cannot dissolve and travel in the water-based bloodstream. Instead, it is transported in the bloodstream by lipoproteins - protein "molecular-suitcases" that 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 (that are 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 LDL particles are large and relatively few in number. In contrast, large numbers of small LDL particles are strongly associated with promoting atheromatous disease within the arteries. (Lack of information on 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. In contrast, 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, another of the major problems of conventional lipid tests.)
The cholesterol molecules present in LDL cholesterol and HDL cholesterol are identical. The difference between the two types of cholesterol derives from the carrier protein molecules; the lipoprotein component.
Cholesterol is primarily synthesized from acetyl CoA through the HMG-CoA reductase pathway in many cells and 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 (68 kg), typical total body content is about 35 g, typical daily internal production is about 1 g 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 reabsorbed into the bloodstream.
Konrad Bloch and Feodor Lynen shared the Nobel Prize in Physiology or Medicine in 1964 for their discoveries concerning the mechanism and regulation of the cholesterol and fatty acid metabolism.
Biosynthesis of cholesterol is directly regulated by the cholesterol levels present, though the homeostatic mechanisms involved are only partly understood. A higher intake from food leads to a net decrease in endogenous production, while lower intake from food has the opposite effect. 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 SRE (Sterol regulatory element) of a number of genes to stimulate their transcription. Among the genes transcribed are the LDL receptor and HMG-CoA reductase. The former scavenges circulating LDL from the bloodstream, whereas HMG-CoA reductase leads to an increase of endogenous production of cholesterol. An excess of cholesterol can build up in the bloodstream and accumulates on the walls of arteries. This build up is what can lead to clogged ateries and eventually to heart attacks and strokes.
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 Ockene et al. showed that there are seasonal variations in cholesterol levels in humans, more, on average, in winter.
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 lecithin and bilirubin gallstones also occur less frequently.
Role in artery disease
In conditions with elevated concentrations of oxidized 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 (though many studies refute this idea). 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. These effects are further complicated by the relative concentration of aymmetric dimethylarginin (ADMA) in the endothelium, since ADMA down-regulates production of nitric oxide, a relaxant of the endothelium. Thus, high levels of ADMA, associated with high oxidized levels of LDL pose a heightened risk factor for vascular disease.
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.
Although relatively rare, an excessively low cholesterol level (hypocholesterolemia) (readings below 160 mg/dL) can increase the risk of depression, cancer, hemorrhagic stroke, respiratory diseases.
Possible causes of low cholesterol are:
- hyperthyroidism, or an overactive thyroid gland
- liver disease
- inadequate absorption of nutrients from the intestines
- celiac disease
- abetalipoproteinemia - A rare genetic disease that causes cholesterol readings below 50mg/dl. It is found mostly in jewish populations.
- hypobetalipoproteinemia-A genetic disease that causes cholesterol readings below 50mg/dl
- Manganese deficiency
Relation of serum lipoproteins and lipids to the ABO blood groups in patients with intermittent claudication
J Cardiovasc Surg (Torino) 1989 Jul;30(4):533-537 Horby J, Gyrtrup HJ, Grande P, Vestergaard A Department of Urology and Vascular Surgery H, University of Copenhagen, Gentofte Hospital, Hellrup, Denmark.
- In the present study we investigated the serum lipoprotein and lipid levels in patients with intermittent claudication (n = 66), divided according to their blood groups in the ABO system (bloodtype A, n = 40 and bloodtype "non-A", n = 26). We again found the expected predominance of blood type A (61%). However, we found no significant differences in any of the biochemical variables between patients belonging to blood group A and "non-A". Fifty-seven of the patients had arteriographies done and the arteriograms were evaluated blindly by a radiologist according to occlusive and stenotic atherosclerotic lesions. However, as previously suggested by other investigators, we were not able to demonstrate any significant differences between the number of occlusions and stenotic lesions when dividing the patients into blood group A and "non-A". The biochemical differences between patients with either occlusive or stenotic atherosclerotic lesions were also tested and found without any significance. In conclusion: the serum lipoprotein and lipid levels in the present study do not give an obvious explanation, why patients with blood group A seem more liable to develop atherosclerosis than those with blood group "non-A".
Investigation of associations between ABO blood groups and coagulation, fibrinolysis, total lipids, cholesterol, and triglycerides
Hum Genet 1979 Apr 27;48(2):221-230 Colonia VJ, Roisenberg I
To investigate possible associations between ABO blood system and coagulability levels, fibrinolysis, total lipids, cholesterol, and triglycerides, the plasma and serum of 300 Rh-positive male blood donors were tested. The tests performed were: RT, PTT, K-PTT, PT, F.V, F.II, F.VII, Complex II, VII, and X, TGT, fibrinogen, HAE 0.2, HAE 0.5, ELT, LIP, Col.1, Col.2 and TRI. Analysis of the laboratory data shows a lower coagulability in O blood group individuals. This result was obtained in coagulation tests (RT, PTT, and K-PTT) specific for factor VIII level. In addition, a higher sensitivity to the in vitro heparin anticoagulant effect in O group individuals was confirmed. Nevertheless, these conclusions are specific for Negroids, the same effects not being observed in Caucasians. None of the other laboratory tests revealed any differences related to either blood group or race.
Longitudinal study of the association between ABO phenotype and total serum cholesterol level in a Japanese cohort
Genet Epidemiol 1992;9(6):405-418
Wong FL, Kodama K, Sasaki H, Yamada M, Hamilton HB Department of Statistics, Radiation Effects Research Foundation, Hiroshima, Japan.
- The relationship between ABO blood phenotype and total serum cholesterol (TC) level was examined in a Japanese population to determine whether an elevated TC level is associated with phenotype A, as has been demonstrated in many West European populations. Such studies in nonwhite populations are scarce, and findings generally failed to demonstrate the relationship. The statistical method of growth curve analysis, through the mixed effect model of Laird and Ware , was used to model age-dependent changes in cholesterol levels within individuals. The effects of the ABO polymorphism in modifying the resultant growth curve are examined. We demonstrate that TC levels are elevated on average by about 4 mg/dl in phenotype A compared to non-A in the Japanese (P < 0.00001), and that this relationship is maintained from early to late adulthood, independent of sex, body mass index, cohort status, or city of residence. Thus, phenotype A individuals may be more predisposed to cardiovascular disease through one of its major risk factors. This is the first study of the ABO-cholesterol association in the Japanese, and the first based on a cohort with longitudinally collected TC data.
Blood groups, serum cholesterol, serum uric acid, blood pressure, and obesity in adolescents
J Natl Med Assoc 1991 Aug;83(8):682-688
Gillum RF Office of Analysis and Epidemiology, National Center for Health Statistics, Hyattsville, Maryland 20782.
- To assess the association of blood groups with coronary risk factors, data were examined from the third cycle of the National Health Examination Survey. In a nationwide sample of more than 6000 black and white adolescents aged 12 to 17 years, ABO blood group, haptoglobin phenotype, selected other genetic markers of blood and secretions, and coronary risk factor levels were measured. Blood group A1 was associated with significantly higher serum total cholesterol levels in white females independent of multiple potential confounders, in white males independent of age and weight, and in southern black females independent of age and weight. ABO blood group was not significantly associated with blood pressure, resting heart rate, or subscapular skinfold thickness. An association with serum uric acid in white males was not independent of weight. In white males only, haptoglobin phenotype 2-2 was associated with significantly higher serum cholesterol levels than 1-1 or 2-1 adjusting for age and weight. No consistent associations were found between Rh types, ABH secretor ability, or group-specific component types and risk factors. This analysis of national data confirms previously reported associations of blood group A with higher serum total cholesterol levels in white adults and adolescents.