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Cholesterol is a waxy steroid of fat produced in liver or intestine, used for the synthesis of hormones and cell membranes and transported in the blood plasma of all mammals. Cholesterol is a very essential structural component of plasma membrane of mammals required for maintaining proper membrane permeability and fluidity. It is also an important agent required for the manufacture of bile acids, steroid hormones and vitamin D. It is the principal steroid synthesized by animals however, smaller amounts are also produced in plants and fungi. Cholesterol is entirely absent among prokaryotes. If its concentration increases in blood then the risk of cardiovascular diseases increases so its level must be kept under control. The word cholesterol has originated from a Greek word and was first discovered by Francois Poulletier de la Salle in gallstones in solid form in 1769 but, chemical identification was done by EugÃ¨ne Chevreul in 1815 who gave the term cholesterine. Physiology Cholesterol participates in the synthesis of male and female steroid hormones especially testosterone and estrogens. About 80% of the body's cholesterol is synthesized by the liver while rest comes from our diet. The major sources of dietary cholesterol are meat, fish, poultry, and dairy products. Among meat, liver is excessively rich in cholesterol content while foods of plant origin lack cholesterol. After consuming a meal, the dietary cholesterol is absorbed from the intestine and packaged inside a protein coat. This cholesterol-protein coat complex is known as chylomicron which is later stored in the liver. Liver bears the potential of regulating cholesterol levels in the blood stream. Cholesterol synthesis starts from simpler elements present in the body. In blood circulation it is transported within lipoproteins and if its level increases then the risk of atherosclerosis increases. Typically for a person weighing 68 kg the total body cholesterol synthesis is 1 g per day. The daily additional dietary intake of cholesterol in the United States is 200-300 mg. The body maintains equilibrium by minimizing the total amount synthesized in the body if the dietary intake of cholesterol increases. Cholesterol is also recycled, it is excreted by the liver via bile into the digestive tract. About 50% of the excreted cholesterol is again reabsorbed in the small intestine and reaches blood stream. Phytosterols can compete with cholesterol reabsorption in the intestine and thus, reduce cholesterol level. Cholesterol is a fat required by the body in small amounts. High blood levels of cholesterol can lead to coronary artery disease and angina. Nitrates are used to relieve angina. Most people require regular tests for knowing blood cholesterol levels that comprise checking of triglycerides, high density lipoproteins (HDL), low density lipoproteins (LDL) and total cholesterol levels. Methods for increasing the levels of good cholesterol or lowering blood cholesterol levels include cholesterol reducing drugs like statins, fibrates, niacin and bile acid resins. These drugs are not able to reverse calcification and if coronary arteries are blocked then heart attack may occur. The
two chief types of cholesterols are high density lipoproteins (HDL) and low density lipoproteins (LDL). For the sake of simplicity HDL is considered as good cholesterol while LDL is known as the bad cholesterol. We can conclude that the bad cholesterol is responsible for forming plaques in the arteries and thus, increases the risk of heart attack. The good cholesterol on the other hand, reverses cholesterol transport by taking it out of the plaque and sending it back to blood circulation for excretion via liver. Types Three major types of lipoproteins are found in the serum of a fasting individual namely, low density lipoproteins (LDL), high density lipoproteins (HDL) and very low density lipoproteins (VLDL). 1. Low density lipoproteins (LDL) or bad cholesterol and its management LDL or bad cholesterol comprises 60-70% of the total serum cholesterol. It is the major atherogenic lipoprotein used in the cholesterol lowering therapy as its higher levels are dangerous. It deposits cholesterol on the walls of arteries resulting in the formation of a hard substance known as cholesterol plaque. This plaque is responsible for the hardening of arterial walls so they become narrow and the process is identified as atherosclerosis. Liver not only manufactures and secretes LDL cholesterol in the blood stream but also removes it from the blood. A large number of active receptors are present on the surface of liver that actively bind to the LDL cholesterol molecules and remove it from blood. A deficiency of LDL receptors is associated with the higher level of these molecules in the blood. A number of advantages are known when the levels of bad cholesterol undergo reduction for example, declination in the formation of new plaques on the walls of the arteries, removal of existing plaques from the arterial walls, narrowed arteries attain their normal shape, avoidance of rupturing of plaques which facilitates formation of blood clots and finally the risk of heart attack is reduced. A number of studies have indicated that the risk of heart attack diminishes by 25% for every 10% drop in the LDL cholesterol level and it is the key factor ensuring that total blood cholesterol level has reached a safer zone. A study carried out with 4,000 individuals has confirmed that the levels of bad cholesterol and risk of heart attack were reduced to about 25% and 42%by using the drug statin. It is profitable that the daily calorie intake of fat must be reduced down to 30% and consumption different kinds of foods rich in carbohydrates, proteins must be increased as the body will convert them into triglycerides which are later stored as fat. Foods rich in saturated fats increase levels of LDL cholesterol in blood stream. Fats may be classified as saturated and unsaturated fats. Saturated fats are easily available in the meat, dairy products and some vegetable oils especially those derived from coconut, palm and cocoa. Therapeutic lifestyle changes adopted for lowering the levels of bad cholesterol include regular exercise, loss of excess body weight and following a diet with low concentration of saturated fats and cholesterol. When lifestyle changes fail to give desired results then medications are taken into consideration. Statins are the most effective drugs giving best results for lowering the levels of bad cholesterol and also reducing the risk of heart diseases. Other drugs that can be used include fibrates like gemfibrozin, resins such as cholestyramine, ezetimibe and Zetia. The National Institute of Health, the American Heart Association and the American College of Cardiology have published some guidelines that can help the medical experts while dealing with cases of high cholesterol.
2. High density lipoproteins (LDL) or good cholesterol and its advantages HDL cholesterol or the good cholesterol as it prevents atherosclerosis by extracting cholesterol from the arterial walls and disposing them through liver. High levels of LDL cholesterol and low levels of HDL cholesterol are associated with the risk of heart diseases. So the levels must be maintained in order to enjoy a happy and healthy life. HDL cholesterol accounts for 20-30% of the total serum cholesterol. Since it reduces the risk of atherosclerosis its level must be checked from time to time. Both heredity and diet have a significant effect on a person's HDL, LDL and total cholesterol levels. Families with low HDL levels are at an elevated risk of heart attack and vice versa. Lifestyle and other factors also influence HDL levels. HDL levels are low in individuals who smoke, are overweight, inactive and suffer from Type II diabetes mellitus. HDL levels are higher in individuals who are lean, exercise regularly and do not smoke. Estrogens also increase HDL levels so women have high HDL cholesterol levels as compared to men. Lowering of the LDL cholesterol level is however easier than elevating the levels of HDL cholesterol. Reducing LDL and raising HDL levels have a beneficial effect on an individual's health. Earlier the researchers were much focused on the ways of reducing the levels of bad cholesterol but with advancement in research it became clear that it is better to raise the levels of good cholesterol as it will automatically reduce bad cholesterol levels. The levels may be raised by weight loss, regular exercise and intake of niacin. Some studies have suggested that drugs like statin when coupled with niacin give better results and women with high levels of HDL have reduced risk of heart attack. The average HDL level for women must be in between 50-55 mg/dL and for men 40-50 mg/dL. The total cholesterol to HDL cholesterol ratio can be of help in estimating the risk of atherosclerosis. An average ratio must be in between 4-5. Studies have indicated that even a small increase in the level of HDL cholesterol can reduce the risk of heart attack. For every 1 mg/dL rise in the HDL cholesterol level the risk of coronary heart disease reduces by 2-4%. However, therapeutic lifestyle changes can help in increasing the HDL levels. When these changes fail to give positive results then medication is taken into account. Regular aerobic exercise, loss of excessive body weight and cessation of smoking are helpful in raising HDL levels. Regular alcohol consumption for example, taking one drink per day can also help in this regard but as alcohol consumption is coupled with many adverse health effects this criterion is not taken into consideration. Effective drugs include gemfibrozil, estrogen and lower doses of statin. A newer medicine, fenofibrate has also given better results and is used in reducing serum triglycerides. 3. Triglycerides or very low density lipoproteins (VLDL) or ugly cholesterol and its effects The ugly cholesterol is a triglyceride rich lipoprotein that accounts for 10-15% of the total serum cholesterol. This cholesterol is produced by liver and some remnants of VLDL seem to promote atherosclerosis similar to that of LDL. Triglyceride is a form of fat transported to the tissue through blood. Body's majority of fatty tissue is composed of triglycerides. Serum triglycerides can be derived from two sources. The first source is the food that we consume for example, if we consume a diet rich in fats then intestine packs some of them while rest is transported to the liver. The second source is the liver itself. When fats are received by the liver, it takes fatty acids released by the fat cells and ties them in triglyceride bundles that are later utilized as fuel. There is a controversy about the fact that whether high levels of triglycerides alone are responsible for coronary heart disease or not.
Other clinical conditions frequently coupled with high triglyceride levels are high blood pressure, obesity, diabetes, chronic kidney, liver and circulatory disease and hypothyroidism. In some individuals elevated triglyceride levels are inherited and this condition is identified as hypertriglyceridemia. The common examples of hypertriglyceridemia include mixed hypertriglyceridemia, familial hypertriglyceridemia and familial dysbetalipoproteinemia. Hypertriglyceridemia can also occur due to some non-genetic factors like obesity, excessive alcohol, diabetes mellitus, kidney disease and use of estrogen containing medicines like birth control pills. The levels can be returned back to normal without medication by taking the help of a physician. The first step involved in the treatment of hypertriglyceridemia includes intake of a diet low in fats with limited consumption of sweets, regular aerobic exercise, loss of excess body weight, reduction of alcohol consumption and quitting smoking. In patients with diabetes mellitus effective control of glucose level is needed. When medications become necessary statins, fibrates and niacin can be used. Fibrates not only reduce the triglyceride levels but also raise the HDL levels and particle size of LDL molecules. Same task is done by niacin but it lowers the levels of Lp (a) cholesterol. Statins on the other hand, reduce both triglyceride and LDL levels but are ineffective in raising HDL levels. A newly launched medicine, fenofibrate has shown promising results in lowering triglyceride and LDL levels as well as raising HDL levels especially in those individuals who show sub-optimal responses with fibrates. In some individuals a mixed dose of fibrate or fenofibrate along with statin is prescribed for better results. Function Cholesterol is needed for building and maintenance of membranes as it modulates membrane fluidity over a wide range of physiological temperatures. The hydroxyl group located on the cholesterol molecule interacts with the polar head groups of membrane phospholipids and sphingolipids and thus, reduces permeability of membrane to protons. Within the cell membrane it also functions in intracellular transport, nerve conduction and cell signaling. Cholesterol is also very essential for the structure and function of invaginated caveolae and clathrin coated pits in endocytosis. Recently, it has been suggested that cholesterol also plays some role in cell signaling process by assisting in formation of lipid rafts in plasma membrane. In many neurons a cholesterol rich myelin sheath is present which is derived from the compact layers of Schwann cell membrane helping in efficient nerve conduction. This layer also provides insulation. Within cells cholesterol also acts as a precursor molecule for several biochemical processes. In liver, cholesterol is converted into bile which is then stored in gallbladder. Bile is rich in bile salts which actively solubilize fat molecules in the digestive tract and thus, aid in intestinal absorption of fat molecules and fat soluble vitamins like A,D,E and K. It is also an essential precursor molecule for the synthesis of vitamin D and steroid hormones. Biosynthesis and Regulation All animal cells manufacture cholesterol but the rate of production varies depending upon the cell type and the organ involved. About 20-25% daily production of cholesterol occurs in the liver and rest in intestines, adrenal glands and reproductive organs. Synthesis of cholesterol within the body starts with one molecule of acetyl- CoA and one molecule of acetoacetyl-CoA that are hydrated to form 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA). The HMG-CoA so formed is reduced to form
mevalonate by the enzyme HMG-CoA reductase. This step is the rate limiting and irreversible step in the cholesterol synthesis. The mevalonate so formed is converted into 3-isopentenyl pyrophosphate in three reactions that need ATP. Mevalonate is then decarboxylated to form isopentenyl pyrophosphate. Then three molecules of isopentenyl pyrophosphate collaborate together to form farnesyl pyrophosphate in the presence of geranyl transferase. Two molecules of farnesyl pyrophosphate join to form squalene in the endoplasmic reticulum and the reaction is catalyzed by squalene synthase. Oxidosqualene cyclase then converts squalene to lanosterol that finally forms cholesterol. The mechanism and regulation of cholesterol was worked out by Konard Bloch and Feodor Lynen for which they received Noble Prize in Physiology or Medicine in 1964. The biosynthesis of cholesterol is under the strict control of the cholesterol levels but homeostatic mechanisms involved in its regulation are partly understood. A higher intake of cholesterol from food results in a net decrease in endogenous production and vice versa. The main mechanism involved comprises sensing of intracellular cholesterol by the protein SREBP (sterol regulatory element-binding protein 1 and 2) located on the endoplasmic reticulum. In the presence of cholesterol this protein binds with two other proteins namely, SCAP (SREBP-cleavage-activating protein) and Insig 1. When the cholesterol level declines Insig 1 dissociates from the SREBPSCAP complex, allowing entry of this complex into the Golgi apparatus, where SREBP is cleaved by S1 and S2 proteases. These proteases are activated by SCAP when cholesterol levels decline. The cleaved SREBP then migrates towards the nucleus to act as a transcription factor and here it binds to the sterol regulatory element (SRE) which stimulates transcription of many genes for example, scavenging of circulating LDL from the blood stream by low density lipoprotein (LDL) receptor and increase in the endogenous production of cholesterol by HMG-CoA reductase. A larger part of this signaling pathway was worked out by Dr. Michael S. Brown and Dr. Joseph L. Goldstein in 1970s for which they received Noble Prize in 1985. Cholesterol synthesis can be terminated when cholesterol levels are high. HMG-CoA reductase bears both cytosolic and membrane domains. The membrane domain is sensitive for the signals responsible for its degradation. Increased concentration of cholesterol causes a change in the oligomerized state of domain that makes it more susceptible to destruction by proteosome. The activity of this enzyme can also be reduced by phosphorylation by an AMP activated protein kinase. Cholesterol is only slightly soluble in water and can be dissolved in water-based blood stream but travels at exceedingly small concentrations. As cholesterol is insoluble in blood it is transported in the circulatory system within the lipoprotein complexes whose outer part is made up of amphiphilic proteins and lipids. Triglycerides and cholesterol esters are carried internally. Lipoproteins provide cholesterol a soluble medium to be transported through blood and for this reason lipoproteins are carried in different forms within blood namely, chylomicrons, very low density lipoproteins (VLDL), intermediate density lipoproteins (IDL), low density lipoproteins (LDL) and high density lipoproteins (HDL). Chylomicrons are the least dense type of cholesterol transporting molecules whose shells are rich in apolipoprotein B-48, apolipoprotein C and E. They carry fats from intestine to muscles and other tissues that require fatty acids for energy. Cholesterol that is not used by the muscles remains in the form of chylomicron remnant which is later taken up by the liver through blood stream. VLDL molecules produced by the liver are loaded with triacylglycerol and cholesterol that are not needed by the liver for the production of bile acids. These molecules contain apolipoprotein B100 and apoplipoprotein E in their shells. During transport the blood vessels cleave and absorb triacylglycerol from IDL molecules that have high concentration of cholesterol. LDL molecules are
the major carriers of cholesterol in the blood and each molecule contains about 1,500 cholesterol esters. The shell of LDL molecule contains only one molecule of apolipoprotein B100 that is recognized by the LDL receptors present on the peripheral tissues. During binding of apolipoprotein B100 many LDL receptors become localized in the clathrin-coated pits. Both LDL and its receptors are internalized by endocytosis to form a vesicle within the cell which then fuses with the lysosome containing lysosomal acid lipase that hydrolyzes cholesterol esters. At this stage cholesterol can be used for the biosynthesis of membrane and can be stored within the cell. Synthesis of LDL receptor is regulated by SREBP protein. When the cell has sufficient amount of cholesterol, LDL receptor synthesis is blocked and no more molecules of cholesterol can enter inside the cell. When the cell is deficient in cholesterol more LDL receptors are formed. When this system is deregulated more LDL molecules without LDL receptors appear in the bloodstream especially near the peripheral tissues. These molecules are then oxidized and taken up by the macrophages forming foam cells and contributing in the formation of atherosclerotic plaques on the walls of the arteries causing heart attack. HDL molecules participate in reverse cholesterol transport as they return cholesterol back to the liver for excretion. Cholesterol is susceptible to oxidation and can easily form oxysterols that are the oxygenated derivatives. Oxysterols can be generated through three mechanisms especially by autoxidation, secondary oxidation to lipid peroxidation and cholesterol metabolizing enzyme oxidation. Oxysterols also participate in bile acid biosynthesis, transport of different forms of cholesterol and regulation of gene transcription. Cholesterol is oxidized by the liver into a variety of bile acids which are in turn conjugated with glycine, taurine, glucuronic acid. A mixture of both conjugated as well as non-conjugated bile acids along with cholesterol is excreted from the liver into bile. About 95% of the bile acids are reabsorbed from the intestines while rest is lost in faeces. The excretion and reabsorption of bile acids form the basis of enterohepatic circulation essential for digestion and absorption of the dietary fats. In certain circumstances, cholesterol crystallizes and forms gallstones especially in the gallbladder. Lecithin and bilirubin gallstones are also known to occur but their percentage is low. Everyday about 1 g of cholesterol is known to enter the colon which comes from diet, bile, desquamated intestinal cells and can be metabolized by the colonic bacteria. Cholesterol is mainly converted into coprostanol which is a nonabsorbable sterol excreted in faeces. A cholesterol reducing bacterium has also been isolated from human faeces. Some cholesterol derivatives are known to generate liquid crystalline cholesteric phase. Dietary sources of cholesterol Animal fats are complex mixtures of triglycerides having lower proportions of phospholipids and cholesterol. Major dietary sources of cholesterol include cheese, egg yolks, beef, pork, shrimp and poultry. Human breast milk also contains sufficient amounts of cholesterol. The amount cholesterol present in the plant sources is lesser when compared with the animal sources. Plant products like peanuts and flax seeds bear phytosterols which are cholesterol like compounds helping to lower serum cholesterol levels. The total fat intake especially in the form of saturated and trans fats play greater role in blood cholesterol rather than the intake of cholesterol itself. Saturated fats are abundantly present in the full fat dairy products, animal fats, chocolate and several types of oils. Trans fats are obtained by the partial hydrogenation of unsaturated fats and do not occur in significant amounts in nature. They are present in good amounts in the margarine, hydrogenated vegetable fats and in many fast foods like snacks, fried or baked goods. Avoiding consumption of
cholesterol rich animal products not only reduces the amount of cholesterol taken through the diet but also reduces the synthesis of cholesterol. Individuals interested to reduce their cholesterol levels through diet must consume less than 7% of their daily energy needs from the animal fats and fewer than 200 mg of cholesterol per day. It is debatable that reduced consumption of dietary fat and cholesterol can lower blood cholesterol levels because any declination in the dietary uptake of cholesterol is compensated by the organs involved in its synthesis so that the levels can be kept constant. Foods that might cholesterol Dietary fibers play a major role in maintaining our health as well as also protect us from a number of diseases like diabetes and heart diseases. Oats, oat bran and oat meal contain a special type of soluble fiber known as beta-glucan that helps in reducing the levels of LDL cholesterol. Oat fibers are different from other fibers in the manner that they reduce the levels of bad cholesterol while the levels of good cholesterol remain unchanged. So we can say that oat fibers help in reducing the risk of coronary heart disease. Studies have also indicated that if individuals with high levels of HDL consume 3 g of soluble oat fiber per day the total cholesterol levels may be declined. Soy protein also protects against heart diseases and hypercholesterolemia as it reduces the bad cholesterol and raises the good cholesterol. It also prevents the oxidation of bad cholesterol so that it may not coagulate on the arterial walls. Several studies have indicated that drinking of green or black teas also reduce the blood cholesterol concentration, blood pressure and inhibit blood clotting and also provide some protection against cardiovascular diseases. Green tea is rich in catechins while black tea contains flavins that inhibit oxidation of bad cholesterol. Tea also contains folic acid that helps in reducing the risk of heart attack and cancer. A person can get 25% of RDA for folic acid by drinking five cups of tea in a day. Several studies have indicated that barely has some unique health promoting effects especially for the heart. The cholesterol fighting efficiency of barley is more pronounced than that of oats. Studies have indicated that it can reduce up to 15% of total cholesterol levels in individuals with elevated cholesterol levels. Barley is also a rich source of beta-glucan which retards fat and cholesterol absorption by the intestines. The fiber is known to bind bile salts and thus, removes cholesterol from the body. Psyllium husk is also a rich source of soluble and insoluble fibers known to reduce the risk of cardiovascular diseases, serum cholesterol, LDL levels, triglycerides and apolipoprotein B. Psyllium husk is rich in a fiber known as beta-sitosterol. Cholesterol testing and reducing high cholesterol The American Heart Association recommends that the cholesterol levels of individuals above 20 years of age must be checked in every five years. A blood sample after 12-hour fasting is taken by the medical expert for the determination of the lipoprotein profile. This determines LDL, HDL, total cholesterol and triglyceride levels. Causes of high cholesterol may vary from person to person and are influenced by the lifestyle and gender of an individual. A number of steps can be taken in order to reduce high cholesterol levels for example loss of excessive body weight. Avoidance of consumption of foods derived from animal fats, regular physical activity and exercise can also help in maintaining low cholesterol levels. Levels of cholesterol in both males and females increase after a certain age and the levels in women tend to increase after menopause. Genes also play an important role in a person's health.
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