How To Understand The Health Benefits Of A High Cholesterol

Transcription

1 FUN WITH CHOLESTEROL Cholesterol, & the Biosynthesis & Regulation of Cholesterol etc For struggling Biochem Students

2 This powerpoint was made for two reasons 1- As resource material for UNIT TWO CRITICAL THINKING PROJECT 2- As resource material for the FINAL PROJECT (if one chooses this topic). Maybe some smart person will kill two birds with one stone!

3 CRITICAL THINKING ASSIGNMENT The Critical Thinking Problems for this week is Critical Thinking Problem #3. Cholesterol is bad and should be eliminated from the diet. Do you agree or disagree? Defend your answer.

4 A Suggested Outline/Plan (you can modify it as you like) a- What is cholesterol? (Show structure) b- Is all cholesterol derived from the diet? If not, how is it made in the body, and transported? (see short story in Doc Sharing, look for equations online) c-list and describe the good/useful features of the steroid cholesterol in the body? d- List and describe the bad / disadvantageous features of cholesterol in the body? e-does regulation of synthesis and transport of cholesterol or any defects that inhibit such regulation play a part in the possible ill effects of cholesterol levels in the body?

5 According to the text.. Remember that cholesterol inhibits its own biosynthesis and activates an enzyme that stores cholesterol in cholesterol ester droplets, thereby exerting some internal balance in the body Remember also that high concentrations of cholesterol inside the cell also inhibit the synthesis of LDL receptors to ensure that the cell will not take up too much cholesterol. Remember also that People with hypercholesterolemia who have a genetic defect in the gene coding for the LDL receptor do not take up as much cholesterol. As a result they accumulate LDL cholesterol in the plasma. This excess plasma cholesterol is then deposited on the artery walls, causing atherosclerosis.

6 f- Conclusion. 1-Is cholesterol really that bad? Or do we have to balance the good things about it by reducing the bad things by maintaining cholesterol levels in the body. 2- Can we intervene with drugs to keep things in balance by decreasing synthesis in the body, or by reducing uptake by the body, so we can reap the benefits of the good about cholesterol? If Yes, can you name any of these drugs, and say how they work?

7 I have posted a file in doc sharing taken from a discussion on a blog that I was involved in on cholesterol synthesis and Lipitor & Vytorin in Doc sharing that you might find useful for this exercise. The mechanism of one type of cholesterol drug is discussed in some detail in the tutorial power point made especially for this exercise.

8 Ideally, this is the level to which we must aspire to think, and the answers we must find, to get the most out of this course. I would suggest that you network among yourselves, by AIM, e mail, telephone etc and chose persons to research the questions on this topic. Post you answers in the discussion board. Then collate and modify what is posted to your taste. Wont that make for a good hot discussion this week? After all this is the sort of information that you want to walk away with from a course such as this in a Health Science degree Program. What do you think? Shall we go for this? Just an idea.

9 What is cholesterol? Cholesterol is a compound produced by the body that has received considerable attention due to its reported link to heart disease. Cholesterol, is one of the most important and abundant steroids in the body. It is the major sterol in humans. It is a waxy substance made by the liver, necessary for normal functioning of the body

10 Cholesterold is a steroid Steroids are a family of organic molecules made of multiple rings. Steroids are simple lipids that contain the fused-ring system commonly called the steroid nucleus. Cholesterol is the most abundant steroid in animals. Many other steroids are synthesized from it.

11 Structure of Cholesterol

12 Steroids are compounds containing the steroid nucleus, which consists of three cyclohexane rings and one cyclopentane ring fused together. The 4 fused rings together are called the cyclopentanophenanthrene ring. The four rings in the steroid nucleus are designated A, B, C, and D. The carbon atoms are numbered beginning with the carbons in ring A and ending with the two methyl groups, as illustrated in the next slide. Attaching other atoms and groups of atoms to the steroid structure forms a wide variety of steroid compounds.

13 You should be able to recognize the basic ring structure of a sterol such as that presented to the right. In fact, because of its importance, you must be able to especially recognize - the sterol illustrated on the right! Note that cholesterol, has a rigid ring system and a short branched hydrocarbon tail Like many steroids, cholesterol has methyl groups at carbon 10 and carbon 13 and a carbon chain at carbon 17 with a double bond between carbon 5 and carbon 6.

14 PART 2

15 CHOLESTEROL

16 So you know what cholesterol is. You know about the 4 fused rings in its structure And you have an idea of what the structure looks like. Can you condense this in to two or three sentences? SURE YOU CAN! SHOW A STRUCTURE.

17 SOURCES OF CHOLESTEROL From liver production and from food CHOLESTEROL IS DERIVED ABOUT EQUALLY FROM THE DIET AND FROM BIOSYNTHESIS. Cholesterol is ingested in the diet but may also be synthesized in the body from acetyl CoA, and carried in the blood to all parts of the body. Found ONLY in foods of ANIMAL origin Cholesterol is typically a product of animal metabolism and therefore occurs in foods of animal origin such as egg yolk, meat, liver, and brain. Cholesterol in the body is obtained from eating these foods. It is also synthesized by the liver from fats, carbohydrates, and proteins. A little more than half the cholesterol of the body arises by synthesis (about 700 mg/d), and the remainder is provided by the average diet. The liver accounts for approximately 10% of total synthesis in humans, the intestines for about another 10%. Virtually all tissues containing nucleated cells are capable of synthesizing cholesterol. The microsomal (endoplasmic reticulum) and cytosol fraction of the cell is mainly responsible for cholesterol synthesis.

18 Cholesterol is not considered an essential nutrient because the body can produce all the cholesterol that it needs. The average American consumes from mg/ day of cholesterol and synthesizes from mg/day. The American Heart Association has recommended that we consume no more than 300 mg of cholesterol a day. The more cholesterol that is consumed the less the body produces and vice versa. This explains why it is so difficult to decrease serum cholesterol by dietary means alone. If you consume less cholesterol, your body produces more to keep the supply constant. REMEMBER: If a diet is high in cholesterol, the liver produces less cholesterol.

19 Cholesterol can be obtained from the diet or it can be synthesized de novo. An adult on a lowcholesterol diet typically synthesizes about 800 mg of cholesterol per day. Normal healthy adults synthesize cholesterol at a rate of approximately 1g/day and consume approximately 0.3g/day. The liver is the major site of cholesterol synthesis in mammals, although the intestine also forms significant amounts.

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21 Cholesterol levels Cholesterol levels related to both saturated fat intake and dietary cholesterol intake Desirable total cholesterol level <200 mg/dl Clinically, cholesterol levels are considered elevated if the total plasma cholesterol level exceeds mg/dl.

22 The actual concentration of cholesterol in plasma of healthy people is usually mg /100 ml. This high solubility of sterol in blood is due to plasma lipoproteins (mainly LDL and VLDL) that have to bind and thereby solubilize large amounts of cholesterol. Cholesterol is present in tissues and in plasma proteins lipoproteins either as free cholesterol or, combined with a long-chain fatty acid, as cholesteryl ester. Free Cholesterol Lipoproteins transport free cholesterol in the circulation, where it readily equilibrates with cholesterol in other proteins and in membranes. Free cholesterol is removed from tissues by HDL and transported to the liver for conversion to bile acids in the process known as reverse cholesterol transport.

23 Desirable levels of serum cholesterol and triacylglycerols in adults

24 WHAT SHOULD WE TO LOOK FOR WHEN MEASURING CHOLESTEROL LEVELS? WHAT IS MOST IMPORTANT IS NOT SO MUCH THE TOTAL LEVELS BUT LEVELS OF THE BADDIES- the LDL levels!!

25 The actual concentration of cholesterol in plasma of healthy people is usually mg /100 ml. This high solubility of sterol in blood is due to plasma lipoproteins (mainly LDL and VLDL) that have to bind and thereby solubilize large amounts of cholesterol. Cholesterol is present in tissues and in plasma proteins lipoproteins either as free cholesterol or, combined with a long-chain fatty acid, as cholesteryl ester. Free Cholosterol Lipoproteins transport free cholesterol in the circulation, where it readily equilibrates with cholesterol in other proteins and in membranes. Free cholesterol is removed from tissues by HDL and transported to the liver for conversion to bile acids in the process known as reverse cholesterol transport.

26 Factors that Lower Cholesterol Soluble Fiber: beans, oats, fruit, and vegetables Monounsaturated Fat:lower LDLs, raise HDLs Aerobic Exercise: increase HDL Antioxidants: lower LDL Fatty fish contain polyunsaturated omega-3 fatty acids

27 Factors that Raise Cholesterol Excess Weight: each 2 pounds of excessive weight adds, on an average, 1 mg/dl to your blood cholesterol. Foods High in Saturated Fat: causes the liver to produce more cholesterol. Smoking: Increases LDL and decreases HDL.

28 Good Cholesterol HDL is Good Cholesterol because it accepts free cholesterol from peripheral tissues e.g; cells in the walls of blood vessels. This cholesterol is converted to cholesterol esters, and part of this is transferred to VLDL; and returned to the liver by IDL & LDL. The liver reutilizes the cholesterol; converting it to bile salts or excretes it directly into the bile HDL, therefore, lower blood cholesterol levels Lower cholesterol levels correlates with low death rate. Coronary atherosclerosis correlates with a high plasma LDL:HDL cholesterol ratio.

29 People who have high levels of LDL & VLDL; often have low HDL; and are prone to atherosclerosis and high incidence of heart attacks and strokes. HDL levels can be increased by exercise and estrogen; exercise is always beneficial to reduce the risk of heart attack and the risks of using unchallenged estrogen therapy in postmenopausal woman. In young woman, the risk of heart attack is lower than in older women Moderate consumption of alcohol is correlated with increased HDL

30 SYNTHESIS OF CHOLESTEROL Cholesterol biosynthesis is necessary for membrane synthesis, and as a precursor for steroid hormone production as well as for vitamin D. Slightly less than half of the cholesterol in the body derives from biosynthesis de novo. Although de novo synthesis of cholesterol occurs in/ by almost all tissues in humans, the capacity is greatest in liver, intestine, adrenal cortex, and reproductive tissues, including ovaries, testes, and placenta. Biosynthesis in the liver accounts for approximately 10%, and in the intestines approximately 15%, of the amount produced each day.

31 How Acetyl-C0A Forms HMG-CoA and Mevalonate: See story in doc sharing! Acetyl-CoA units are converted to mevalonate by a series of reactions that begins when two moles of acetyl-coa are condensed in a reversal of the thiolase reaction, forming acetoacetyl-coa. Then a third molecule of acetyl-coa is added to acetoacetyl-coa to form 3-hydroxy-3methylglutaryl-CoA (HMG-CoA) by the action of HMG-CoA synthase. Then HMG-CoA is converted to mevalonate by HMGCoA reductase (this enzyme is bound to the endoplasmic reticulum). The reaction catalyzed by HMG-CoA reductase is the rate limiting step of cholesterol biosynthesis, and this enzyme is subject to complex regulatory controls.

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34 A relatively constant level of cholesterol in the body ( mg/dl) is maintained primarily by controlling the level of de novo synthesis. The level of cholesterol synthesis is regulated in part by the dietary intake of cholesterol. Regulation of HMG-CoA reductase activity (the ratelimiting enzyme in cholesterol synthesis) is the primary means for controlling the level of cholesterol biosynthesis. The enzyme is controlled in multiple ways. All of the regulatory mechanisms are modulated by receptors that sense the presence of cholesterol in the blood.

35 Cholesterol GOOD! Basis for the formation of sex hormones Used in cell membranes Important constituent of membranes They are hormones signaling molecules and messenger molecules BAD! Cause a problem when it is deposited in the lining of blood vessels May lead to arteriosclerosis and heart attacks

36 PART 3 A

37 THE GOOD Make a list of the good things about cholesterol, and then DISCUSS THEM! Use this powerpoint and your text! Cholesterol is an extremely important biological molecule that has roles in membrane structure as well as being a precursor for the synthesis of the steroid sex hormones, bile acids and vitamin D. Cholesterol from both diet and synthesis is utilized in the formation of membranes and in the synthesis of the steroid hormones and bile acids. The greatest proportion of cholesterol is used in bile acid synthesis.

38 Cholesterol is a precursor for other important steroid molecules, such as the bile salts steroid hormones, and vitamin D These are all important derivatives of cholesterol. Insulates nerve tissue Integral part of cell walls

39 Cholesterol is not just a greasy molecule that causes heart attacks. It is the most abundant sterol, and the major sterol in humans and a component of virtually all plasma and intracellular membranes. Cholesterol is especially abundant in myelinated structures of brain and central nervous system but is present in small amounts in the inner membrane of mitochondria. Cholesterol is an ubiquitous and essential structural component of mammalian cellular membranes, myelin sheath, and brain and nerve tissue, and of the outer layer of plasma lipoproteins.

40 Cholosterol is primarily found in membranes - increasing fluidity of the membrane. The presence of cholesterol in a phospholipid membrane inhibits transition to the crystalline state. However interaction with the relatively rigid cholesterol decreases the mobility of hydrocarbon tails of phospholipids. Phospholipid membranes that include cholesterol have a fluidity intermediate between the liquid crystal and crystal states. Cholesterol is thought to play a role in buffering the temperaturedependent fluidity of lipid bilayers by stiffening them at warmer temperatures but loosening them (by disrupting van der Waals interactions between phospholipids) at lower temperatures. It is an extremely important biological molecule that has an important role as a precursor for the biosynthesis of all of the other steroids in the body such as steroid hormones, including the mineralocorticoids, glucocorticoids and sex hormones bile acids, bile salts, and vitamin D; also myelin synthesis. All steroid hormones are structurally related to and chemically derived from cholesterol, despite the fact that they have widely different physiological properties It is also found in the liver, and skin, where it forms vitamin D. In the adrenal gland, it is used to synthesize steroid hormones.

41 WHY CHOLESTEROL IS GOOD AND NEEDED IN MEMBRANES Cholesterol is very hydrophobic. But it has one polar group, a hydroxyl, which makes it an amphipathic lipid with very low solubility in water; at 25 C, the limit of solubility is approximately 0.2 mg/10o ml, or 4.7 mm. Cholesterol inserts into bilayer membranes with its hydroxyl group oriented toward the aqueous phase and its hydrophobic ring system adjacent to fatty acid tails of phospholipids. The hydroxyl group of cholesterol forms hydrogen bonds with polar phospholipid head groups

42 AMPHIPATHIC LIPIDS SELF-ORIENT AT OIL: WATER INTERFACES In general, lipids are insoluble in water, since they contain a predominance of nonpolar (hydrocarbon) groups. However, fatty acids, phospholipids, sphingolipids, bile salts, and, to a lesser extent, cholesterol contain polar groups. Therefore, part of the molecule is hydrophobic, or water-insoluble, and part is hydrodrophilic, or water-soluble. Such molecules are described as amphipathic (Figure 16 29). They come oriented at oil-water interfaces with the polar group in the water phase and the nonpolar groups in the oil phase. A bilayer of such amphipathic lipids has been regarded as a basic structure in biological membranes. When a critical concentration of these lipids is present in an aqueous medium they form micelles. Aggregations of bile salts into micelles and liposomes, and the formation of mixed micelles with the products of fat digestion are important in facilitating absorption of lipids from the intestine. Liposomes consist of spheres of lipid bilayers that enclose part of theaqueous medium. They are of potential clinical use particularly when combined with tissue-specific antibodies, as carriers of drugs in the circulation, targeted to specific organs, eg, in cancer therapy. In addition, they are being used for gene transfer into vascular cells and as carriers for topical and transdermal delivery of drugs and cosmetics. Emulsions are much larger particles, formed usually by nonpolar lipids in an aqueous medium. These are stabilized emulsifying agents such as amphipathic lipids (eg. lecithin), which form a surface layer separating the main bulk of the nonpolar material from the aqueos phase (Figure 16 29).

43 Formation of lipid membranes, micelles, emulsions, and liposomes from amphipathic lipids, eg, phospholipids.

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45 Cholesterol=> bile salts & steroid hormones

46 Cholesterol is also abundant in bile where the normal concentration is 390 mg/100 Only 4% of cholesterol in bile is esterified to a longchain fatty acid. Bile does not contain appreciable amounts of lipoproteins and solubilization of free cholesterol is achieved in part by the detergent property of phospholipids present in bile that are produced in liver. Bile salts, which are metabolites of cholesterol, also aid in solubilizing cholesterol in bile. Cholesterol also appears to protect membranes of the gallbladder from potentially irritating or harmful effects of bile salts.

47 DEGRADATION OF CHOLESTEROL The ring structure of cholesterol cannot be metabolized to CO2 and H20 in humans. Rather, the intact sterol ring is eliminated from the body by: 1- conversion to bile acids, which are excreted in the feces, and 2- secretion of cholesterol into the bile, which transports it to the intestine for elimination. Some of the cholesterol in the intestine is modified by bacteria before excretion. The primary compounds made are reduced derivatives of cholesterol that is, coprostanol and cholestanol, the only difference between these two isomers being the orientation of the hydrogen atom between the A and B rings. Together, these three compounds make up the bulk of neutral fecal sterols.

48 Bile Acids Synthesis, Utilization and Elimination The end products of cholesterol utilization are the bile acids, synthesized in the liver. Synthesis of bile acids is one of the predominant mechanisms for the excretion of excess cholesterol. However, the excretion of cholesterol in the form of bile acids is insufficient to compensate for an excess dietary intake of cholesterol.

49 Bile Salts Bile salts play a role in digestion. They are synthesized form cholesterol in the liver and stored in the gallbladder. During digestion, bile salts break down (emulsify) nonpolar fat globules, aiding in digestion and absorption of dietary lipids. Bile salts have one polar and one nonpolar face.

50 Clinical Significance of Bile Acid Synthesis Bile acids perform four physiologically significant functions: 1. their synthesis and subsequent excretion in the feces represent the only significant mechanism for the elimination of excess cholesterol. 2. bile acids and phospholipids solubilize cholesterol in the bile, thereby preventing the precipitation of cholesterol in the gallbladder. 3. they facilitate the digestion of dietary triacylglycerols by acting as emulsifying agents that render fats accessible to pancreatic lipases. 4. they facilitate the intestinal absorption of fatsoluble vitamins.

51 Are the above an important feature of cholesterol in the body? Can you summarize this information? LOOK AT THE PICTURES THAT FOLLOW AND SEE IF YOU CAN SAY WHAT THEY ARE SAYING AND PUT IT IN YOUR ESSAY? There may be some repetition but don t worry about that. Sift out the main ideas.

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53 Structures of primary bile acids

54 After secretion into the intestine, the bile salts may be deconjugated and dehydroxylated by bacteria, forming secondary bile salts. Insoluble and mainly excreted.

55 Synthesis of bile salts

56 DO YOU SEE WHAT WOULD HAPPEN IF WE DIDN T HAVE ANY CHOLESTEROL TO BREAK DOWN TO MAKE BILE SALTS. BUT A chronic disturbance in phospholipid metabolism in liver can result in deposition of cholesterol-rich gallstones.

57 Steroid Hormones The steroid hormones, which include the sex hormones and the adrenocortical hormones, are closely related in structure to cholesterol and depend on cholesterol for their synthesis. Cholesterol is the precursor of 5 classes of steroid hormones 1. glucocorticoids (e.g. cortisol) 2. mineralocorticoids (e.g. aldosterone) Sex steroids: 3. androgens 4. estrogens 5. progestins

58 HERE ARE SOME NICE PICTURES OF THE STEROID HORMONES? CAN YOU SAY BRIEFLY HOW STEROID HORMONES ARE FORMED AND WHAT EACH ONE DOES? AND DECIDE IF THIS IS A GOOD THING FOR CHOLESTEROL?

59 Part 3 B

60 Bile acids Cholesterol Progesterone Glucocorticosteroid Mineralocorticosteroid Androgens Estrogens

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62 Synthesis and secretion occur in the adrenal cortex (cortisol, aldosterone), ovaries and ovarian corpus luteum (estrogens, progestins), and testes (testosterone). Steroid hormones are transported by the blood from their sites of synthesis to their target organs. Because of their hydrophobicity, they must be complexed with a plasma protein; for example, plasma albumin can act as a nonspecific carrier for the steroid hormones. However, specific plasma steroid-carrier proteins bind the steroid hormones more tightly than does albumin; for example, transcortin is responsible for transporting cortisol and corticosterone, and sex hormone-binding protein transports the sex steroids.

63 and androsterone, promote the growth of muscle and of facial hair and the maturation of the male sex organs and sperm. The estrogens, a group of female sex hormones, direct the development of female sexual characteristics: the uterus increases in size, fat is deposited in the breasts, and the pelvis broadens. Progesterone prepares the uterus for the implantation of a fertilized egg. If an egg is not fertilized, the levels of progesterone and estrogen drop sharply, and menstruation follows. Synthetic forms of the female sex hormones are used in birth-control pills. As with other kinds of steroids, side effects include weight gain and a greater risk of forming blood clots. The structures of some steroid hormones follow:

64 Steroids: Human Sex Hormones

65 Steroids: Adrenocorticoids

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71 Pathways for the formation of progesterone, cortisol, and aldosterone

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75 The importance of the last group of slides is that they are a lesson in the concept of STRUCTURE ACTIVITY RELATIONSHIP- a very important concept in Biochemistry.

76 Adrenal Corticosteroids The adrenal glands, located on the top of each kidney, produce the corticosteroids. Aldosterone, a mineralocorticoid, is responsible for electrolyte and water balance by the kidneys. Cortisone, a glucocorticoid, increases the blood glucose level and stimulates the synthesis of glycogen in the liver from amino acids. Synthetic corticoids such as prednisone are derived from cortisone and used medically for reducing inflammation and treating asthma and rheumatoid arthritis, although precautions are given for long-term use.

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78 Some Corticosteroids widely in Medicine! are used

79 Part 4 a First part of the BAD

80 THE BAD The root of the cause of cholesterol problems are 1-SOME FOLK ABUSE FAT INTAKE => heart disease 2 If it the excess cholesterol is not degraded => gall stones 3 Some people have a genetic problem with the system that regulates cholesterol synthesis and they produce excessive amounts which they find difficult to get out of the blood system ( also caused by 1 above right?.

81 Both dietary cholesterol and that synthesized de novo are transported through the circulation in lipoprotein particles. The same is true of cholesteryl esters, the form in which cholesterol is stored in cells. The synthesis and utilization of cholesterol must be tightly regulated in order to prevent overaccumulation and abnormal deposition within the body.

82 Of particular importance clinically is the abnormal deposition of cholesterol and cholesterol-rich lipoproteins in the coronary arteries. High levels of cholesterol are associated with the accumulation of lipid deposits (plaque) that line and narrow the coronary arteries. Such deposition, eventually leading to atherosclerosis, is the leading contributory factor in diseases of the coronary arteries.

83 Some people have a genetic problem with the system that regulates cholesterol synthesis and they produce excessive amounts. In order to enter cells, cholesterol must react with receptors on the cell surface. These receptors require a certain concentration of serum cholesterol before they can absorb it. If the receptors do not function efficiently, more must be secreted into the blood to satisfy the needs of cells. These people generally have greatly elevated serum cholesterol levels. This is of concern because high serum cholesterol is a risk factor for coronary heart disease.

84 Coronary Heart Disease. The greatest cause of death in America is coronary heart disease. This is a complex illness with many causes that usually develops over a long period of time. A number risk factors have been related to the incidence of coronary heart disease. None of these factors can be called a cause of the disease and not all people with a given risk factor or factors will develop the disease. The risk factors have been shown to, on the average, increase the risk of developing coronary heart disease.

85 High blood cholesterol increases risk of CAD Saturated fat intake increases blood cholesterol more then dietary cholesterol intake Triglycerides Fat molecules in blood Predominant storage form of body fat Optimal level between mg/dl Increased by excess intake of refined sugars, starches and alcohol Contributes to atherosclerosis by increasing blood clumping.

86 PATHOPHYSIOLOGY OF ATHEROSCLEROSIS

87 LDL Cell Cell plenty of cholesterol Degeneration and death Macrophage Phagocytosis Foam cell Fibroblast Proliferation Growth factors Fatty streak Muscle cell Proliferation Fibrous plaque Calcification Complex lesion

88 Excess cholesterol forms plaque that can block an artery, resulting in a heart attack. Below, we see a normal, open artery which shows no buildup of plaque

89 Here, we see an artery that is almost completely clogged by atherosclerotic plaque.

90 Progression of atherosclerotic plaque formation in endothelial cells of blood vessels.

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92 An atherosclerotic plaque. A plaque (marked by an arrow) blocks most of the lumen of this blood vessel. The plaque is rich in cholesterol.

93 The synthesis and utilization of cholesterol must be tightly regulated in order to prevent over-accumulation and abnormal deposition within the body. Of particular importance clinically is the abnormal deposition of cholesterol and cholesterol-rich lipoproteins in the coronary arteries. Such deposition, eventually leading to atherosclerosis, is the leading contributory factor in diseases of the coronary arteries. Atherosclerosis is a disorder of the arterial wall characterized by accumulation of cholesteryl esters in cells derived from the monocyte macrophage line, smooth muscle cell proliferation, and fibrosis

94 Lower blood cholesterol levels have been correlated with a lower death rate This figure shows a large number of deaths in patients with plasma cholesterol levels in the range mg/dl. However, it does not show the death rate below 160-mg/dl.

95 Some Risk Factors for Coronary Heart Disease (CHD)

96 Bile salt deficiency: cholelithiasis The bile salts are synthesized in the liver from cholesterol but they are stored in the gall- bladder. From our Anatomy, we know that the bile canaliculi join with the bile ductules, which then form the bile ducts. Bile acids are carried from the liver through these ducts to the gallbladder, where they are stored for future use. The movement of cholesterol from the liver into the bile must be accompanied by the simultaneous secretion of phospholipid and bile salts. If this coupled process is disrupted and more cholesterol enters the bile than can be solubilized by the bile salts and lecithin present, the cholesterol may precipitate in the gallbladder, initiating the occurrence of cholesterol gallstone disease cholelithiasis. Thus when large amounts of cholesterol accumulate in the gallbladder, cholesterol can precipitate out and form gallstones, as illustrated in the next slide.

97 When cholesterol exceeds its saturation level in the bile, gallstones may form. Gallstones are composed of almost 100% cholesterol with some calcium salts, fatty acids, and phospholipids.

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99 REMEMBER! Besides being a major constituent of gallstones, cholesterol s chief role in pathologic processes is as a factor in the genesis of atherosclerosis of vital arteries, causing cerebrovascular, coronary, and peripheral vascular disease.

100 Part 4 B Second part of the bad

101 Here, we see an artery that is almost completely clogged by atherosclerotic plaque.

102 Progression of atherosclerotic plaque formation in endothelial cells of blood vessels.

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104 An atherosclerotic plaque. A plaque (marked by an arrow) blocks most of the lumen of this blood vessel. The plaque is rich in cholesterol.

105 The synthesis and utilization of cholesterol must be tightly regulated in order to prevent over-accumulation and abnormal deposition within the body. Of particular importance clinically is the abnormal deposition of cholesterol and cholesterol-rich lipoproteins in the coronary arteries. Such deposition, eventually leading to atherosclerosis, is the leading contributory factor in diseases of the coronary arteries. Atherosclerosis is a disorder of the arterial wall characterized by accumulation of cholesteryl esters in cells derived from the monocyte macrophage line, smooth muscle cell proliferation, and fibrosis

106 Lower blood cholesterol levels have been correlated with a lower death rate This figure shows a large number of deaths in patients with plasma cholesterol levels in the range mg/dl. However, it does not show the death rate below 160-mg/dl.

107 Some Risk Factors for Coronary Heart Disease (CHD)

108 Bile salt deficiency: cholelithiasis The bile salts are synthesized in the liver from cholesterol but they are stored in the gall- bladder. From our Anatomy, we know that the bile canaliculi join with the bile ductules, which then form the bile ducts. Bile acids are carried from the liver through these ducts to the gallbladder, where they are stored for future use. The movement of cholesterol from the liver into the bile must be accompanied by the simultaneous secretion of phospholipid and bile salts. If this coupled process is disrupted and more cholesterol enters the bile than can be solubilized by the bile salts and lecithin present, the cholesterol may precipitate in the gallbladder, initiating the occurrence of cholesterol gallstone disease cholelithiasis. Thus when large amounts of cholesterol accumulate in the gallbladder, cholesterol can precipitate out and form gallstones, as illustrated in the next slide.

109 When cholesterol exceeds its saturation level in the bile, gallstones may form. Gallstones are composed of almost 100% cholesterol with some calcium salts, fatty acids, and phospholipids.

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111 REMEMBER! Besides being a major constituent of gallstones, cholesterol s chief role in pathologic processes is as a factor in the genesis of atherosclerosis of vital arteries, causing cerebrovascular, coronary, and peripheral vascular disease.

112 Part five

113 THE UGLY! ANABOLIC STEROIDS MAY BE CONSIDERED A BAD THING ABOUT CHOLESTEROL.

114 Anabolic Steroids Some of the physiological effects of testosterone are to increase muscle mass and decrease body fat Derivatives of testosterone called anabolic steroids that enhance these effects have been synthesized. Although they have some medical uses anabolic steroids have been used in rather high dosages by some athletes in an effort to increase muscle mass Such use is illegal Use of anabolic steroids in attempting to improve athletic strength can cause side effects including hypertension fluid retention increased hair growth sleep disturbances and acne. Over a long period of time, their use can be devastating and may cause irreversible liver damage and decreased sperm production.

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116 BIOCHEMISTRY BASIS FOR TREATMENT OF HIGH CHOLESTEROL LEVELS

117 Since some people have a genetic problem with the system that regulates cholesterol synthesis and they produce excessive amounts we might want to know enough about the synthesis of cholesterol to advise the Pharmaceutical industry, to help. Agreed? => Lipitor & other statins. Maybe they can help with increased uptake from the blood stream too? => Vytorin

118 We all agree that cholesterol is synthesized from Acetyl CoA Acetyl CoA utilized for cholesterol biosynthesis can be obtained from the following sources 1-the beta -oxidation of fatty acids in the mitochondria 2- the oxidation of ketogenic amino acids such as leucine and isoleucine 3- the pyruvate dehydrogenase reaction in the mitochondria. WHAT IS THE MOST IMPORTANT THING TO NOTE is that the first compound unique to cholesterol biosynthesis is mevalonic acid since first two reactions in cholesterol biosynthesis are shared by the path that produces ketone bodies. NOTE that the rate limiting step occurs at the 3-hydroxy-3methylglutaryl-CoA (HMG-CoA) reducatse catalyzed step THAT S WHY WE HAVE TO BLOCK THIS ENZYME AND STOP MEVALONATE PRODUCTION

119 Overview of cholesterol synthesis Cholesterol can be synthesized by most cells. The liver and small intestine are especially active in synthesizing cholesterol. The precursor of cholesterol is acetyl CoA, which can be produced from glucose, fatty acids, or amino acids. Two molecules of acetyl CoA form acetoacetyl CoA, which condenses with another molecule of acetyl CoA to form hydroxymethylglutaryl CoA (HMGCoA). Reduction of HMG-CoA produces mevalonate. This reaction, catalyzed by HMG-CoA reductase, is the major rate-limiting step of cholesterol synthesis.

120 Overview of cholesterol synthesis

121 WE ARE ONLY INTERESTED IN THE PATHWAY FROM ACETYL COA TO MEVALONATE AND THE FACT THAT WE CAN BLOCK THE ENZYME HMG-CoA Reductase that catalyzes this the with STATINS WE WILL REPEAT THIS WITH SEVERAL PICTURES

122 Reduction of HMG-CoA to mevalonate. IF YOU CAN STOP MEVALONATE BEING MADE--- NO CHOLESTEROL CAN BE MADE AT ALL!

123 Same reaction! IF YOU CAN STOP MEVALONATE BEING MADE--- NO CHOLESTEROL CAN BE MADE AT ALL! This slide is showing that cholesterol itself can block this reaction. Why? FOR REGUATION. When we make enough cholesterol in our bodies, the cholesterol itself switches off the synthesis of mevalonate by FEEDBACK INHIBITION. The same enzyme is inhibited by cholesterol that WE ATTACK WITH DRUGS LIKE LIPITOR!

124 Inhibition of mevalonate by drugs is used in therapy of patients with high cholesterol levels! Lovostatin and mevastatin are reversible inhibitors of HMG CoA reductase (CALLED STATTINS). These drugs are used to decrease plasma cholesterol levels in hypercholesterolemia

125 Such drugs BLOCKS the rest of the metabolic pathway that takes mevalonate to cholesterol. REMEMBER: NO MEVALONATE => NO CHOLESTEROL Note also once more that when the body makes enough cholesterol it blocks the rest of the pathway by stopping the further conversion of HMG-CoA to mevalonate!

126 Biosynthesis of mevalonate. The synthesis of HMGCoA reductase is inhibited by the fungal metabolites mevastatin (compactin), lovastatin (mevinolin), provastatin, and simvastatin. The open and solid circles indicate the fate of each of the carbons in the acetyl moiety of acetylc0a.

127 Lovastatin is a competitive inhibitor of HMG-CoA reductase. The part of the structure that resembles the 3-hydroxy-3-methylglutaryl moiety is shown in red. By knowing the structure of mevalonate, biochemists could synthesize the statins to look like mevalonate. This fools the enzmye sort off and blocks the further formation of mevalonate.

128 The central role of HMG CoA reductase in cholesterol homeostasis is evidenced by the effectiveness of a family of drugs called statins to lower plasma cholesterol Statins (e.g., lovastatin, pravastatin, fluvastatin, cerivastatin, and atorvastatin) inhibit HMG CoA reductase activity, particularly in liver, and commonly lower total plasma cholesterol by as much as 50%. TO REPEAT: Lovastatin and the other statins are reversible, competitive inhibitors of HMG CoA reductase which are used to decrease plasma cholesterol levels in patients with hypercholesterolemia.

129 To reduce the high levels of VLDL in blood; low carbohydrate diets may decrease triglyceride and cholesterol levels. Triglyceridesof VLDL are synthesized in the liver mainly from dietary carbohydrate. As VLDL are secreted from the liver, they carry cholesterol into the blood. Blood cholesterol levels can be controlled with diet therapy; higher levels can also be treated by reductase inhibitor (HMG-CoA) Pravastatin ; which decrease the rate of synthesis of cholesterol in cells. As cellular cholesterol levels decreases, the synthesis of LDL receptors increases. As the number of receptors rises on the cell surface, the up take of LDL is increased; and consequently the blood level of LDL cholesterol decreases.

130 Alternative to drug treatment --- a high-fiber diet is a moderately effective means of decreasing LDL cholesterol. Some types of dietary fiber are thought to reduce absorption of bile acids from the ileum just by simply increasing the bulk of the intestinal contents. For example,cholestyramine, increases excretion of bile acids and leads to an increased conversion of cholesterol to bile acids and upregulation of hepatic LDL receptors.

131 The regulation of cholesterol biosynthesis is effected by 1 Control of gene expression 2 Rate of enzyme degradation and 3 Phosphorylation-dephosphorylation. 4- Drugs The first two control mechanisms are exerted by cholesterol itself. Cholesterol acts as a feed-back inhibitor of preexisting HMG-CoA reductase as well as inducing rapid turn-over of the enzyme. In addition, when cholesterol is in excess the amount of mrna for HMG-CoA reductase is reduced as a result of decreased expression of the gene. The exact mechanism for this cholesterolinduced regulation of gene activity is not known.