Cholesterol blood levels synthesis

The answer is a. (Hardman, pp 885-887.) Lovastatin decreases cholesterol synthesis in the liver by inhibiting HMG-CoA reductase, the rate-limiting enzyme in the synthetic pathway This results in an increase in LDL receptors in the liver, thus reducing blood levels for cholesterol. The intake of dietary cholesterol must not be increased, as this would allow the liver to use more exogenous cholesterol and def eat the action of lovastatin. 

The clinical problems that arise in the menopause are hot flushes, sweating, depression, decreased libido, increased risk of cardiovascular disease and osteoporosis. The latter results in increased incidence of hip, radial and vertebral fractures. Oestrogen is one factor controlling synthesis of active vitamin D and osteoporosis is in part due to a deficiency of vitamin D. Not surprisingly, to reduce these problems, administration of oestrogen is recommended (known as hormone replacement therapy or HRT). HRT reduces some of the risk factors for coronary artery disease since it reduces blood pressure and decreases the blood level of LDL-cholesterol and increases that of HDL-cholesterol. However, there is considerable debate about whether HRT increases the risk of breast or endometrial cancer. 

Drugs Drugs that lower the blood levels of cholesterol are frequently used as part of the treatment these include (i) Oral bile acid binding exchange resins. Resins such as cholestyramine are effective because, when taken by mouth, they prevent the reabsorption of bile acids in the lower small intestine, so that they are excreted in the faeces. Since bile acids are formed in the liver from cholesterol, synthesis of more acids requires more cholesterol uptake by the liver from the blood, which occurs via LDL-cholesterol, so that the concentration of the latter is decreased. 

The weight of evidence supports the conclusion that the more expressed inhibition of HMG-CoA reductase by a higher statin blood level reduces the concentrations of other essential products, primarily of isoprenylated proteins and possibly ubiquinone, synthetized downstream from mevalonic acid within the peripheral cells. In parallel, it was also recognized that statins exert pleiotropic effects in various cells far beyond the originally described inhibition of hepatic cholesterol synthesis. All of these effects are considered to be class-specific for the statins. It is important to emphasize that the frequency of untoward side effects observed with the various statins can be related to their potency, the number of metabolic inter-... 

The reaction in which HMG-CoA reductase reduces HMG to form mevolonate is a rate-limiting step in cholesterol synthesis. Statins, inhibitors of this enzyme, act to lower blood levels of cholesterol in patients. 

In addition to dietary therapy, aimed at reducing her blood cholesterol levels, Ann Jeina was treated with pravastatin, an HMG-CoA reductase inhibitor. The HMG-CoA reductase inhibitors decrease the rate of synthesis of cholesterol in cells. As cellular cholesterol levels decrease, the synthesis of LDL receptors increases. As the number of receptors rises on the cell surface, the uptake of LDL is increased. Consequently, the blood level of LDL cholesterol decreases. 

HDL is considered to be the good cholesterol, because it accepts free cholesterol from peripheral tissues, such as cells in the walls of blood vessels. This cholesterol is converted to cholesterol ester, part of which is transferred to VLDL by CETP, and returned to the liver by IDL and LDL. The remainder of the cholesterol is transferred directly as part of the HDL molecule to the liver. The liver reutilizes the cholesterol in the synthesis of VLDL, converts it to bile salts, or excretes it directly into the bile. HDL therefore tends to lower blood cholesterol levels. Lower blood cholesterol levels correlate with a lower rates of death of atherosclerosis. 

To pay attention to nicotinic acid, which at high doses (I to 6 g per day) significally reduces blood levels of cholesterol by enzymatic mechanisms at the level of synthesis in the liver and by the conversion of bile acids, would mean to displace the question into a pharmacological basis, which is not our intention nor competence. 

Rice bran is the richest natural source of B-complex vitamins. Considerable amounts of thiamin (Bl), riboflavin (B2), niacin (B3), pantothenic acid (B5) and pyridoxin (B6) are available in rice bran (Table 17.1). Thiamin (Bl) is central to carbohydrate metabolism and kreb s cycle function. Niacin (B3) also plays a key role in carbohydrate metabolism for the synthesis of GTF (Glucose Tolerance Factor). As a pre-cursor to NAD (nicotinamide adenine dinucleotide-oxidized form), it is an important metabolite concerned with intracellular energy production. It prevents the depletion of NAD in the pancreatic beta cells. It also promotes healthy cholesterol levels not only by decreasing LDL-C but also by improving HDL-C. It is the safest nutritional approach to normalizing cholesterol levels. Pyridoxine (B6) helps to regulate blood glucose levels, prevents peripheral neuropathy in diabetics and improves the immune function. 

Inhibit Enzymes Many drugs are competitive inhibitors of key enzymes in pathways. The statin drugs (lovastatin, simvastatin), used to control blood cholesterol levels, competitively inhibit 3-hvdroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase in cholesterol biosynthesis. Methotrexate, an antineoplastic drug, competitively inhibits dihydrofolate reductase, depriving the cell of active folate needed for purine and deoxythymidine synthesis, thus interfering with DNA replication during S phase. 

Treatment of Hypercholesterolemia Cholestyramine and other drugs that increase elimination of bile salts force the liver to increase their synthesis from cholesterol, thus lowering the internal level of cholesterol in the hepatocytes. Decreased cholesterol within the cell increases LDL receptor expression, allowing the hepatocyte to remove more LDL cholesterol from the blood. HMG-CoA reductase inhibitors such as lovastatin and simvastatin inhibit de novo cholesterol synthesis in the hepatocyte, which subsequently increases LDL receptor expression. 

The second thing that happens is a very good thing. The liver upregulates its LDL receptor level. In snm, the liver does the two things that it can do to maintain an adequate source of its cholesterol pump up the synthesis (to normal or slightly subnormal rates only) and pnmp np the seqnestration of cholesterol from the blood LDLs. The net effect is that the rate of excretion of cholesterol from the body is increased due to the increase in the nnmber of LDL receptors expressed on hepatic cells without compromising the availability of cholesterol to meet cellular needs. 

One role of high density lipoprotein (HDL) is to collect unesterified cholesterol from cells, including endothelial cells of the artery walls, and return it to the liver where it can not only inhibit cholesterol synthesis but also provide the precursor for bile acid formation. The process is known as reverse cholesterol transfer and its overall effect is to lower the amount of cholesterol in cells and in the blood. Even an excessive intracellular level of cholesterol can be lowered by this reverse transfer process (Figure 22.10). Unfortunately, the level of HDL in the subendothelial space of the arteries is very low, so that this safety valve is not available and all the cholesterol in this space is taken up by the macrophage to form cholesteryl ester. This is then locked within the macrophage (i.e. not available to HDL) and causes damage and then death of the cells, as described above. 

The answer is D. This patient s tests indicate that he has severe hypercholesterolemia and high blood pressure in conjunction with atherosclerosis. The deaths of several of his family members due to heart disease before age 60 suggest a genetic component, ie, familial hypercholesterolemia. This disease results from mutations that reduce production or interfere with functions of the LDL receptor, which is responsible for uptake of LDL-cholesterol by liver cells. The LDL receptor binds and internalizes LDL-choles-terol, delivers it to early endosomes and then recycles back to the plasma membrane to pick up more ligand. Reduced synthesis of apoproteins needed for LDL assembly would tend to decrease LDL levels in the bloodstream, as would impairment of HMG CoA reductase levels, the rate-limiting step of cholesterol biosynthesis. Reduced uptake of bile salts will also decrease cholesterol levels in the blood. 

In the past decade, eight inherited disorders have been linked to specific enzyme defects in the isoprenoid/cholesterol biosynthetic pathway after the finding of abnormally increased levels of intermediate metabolites in tissues and/or body fluids of patients (Table 5.1.1) [7, 9, 10]. Two of these disorders are due to a defect of the enzyme mevalonate kinase, and in principle affect the synthesis of all isoprenoids (Fig. 5.1.1) [5]. The hallmark of these two disorders is the accumulation of mevalonic acid in body fluids and tissues, which can be detected by organic acid analysis, or preferably, by stable-isotope dilution gas chromatography (GC)-mass spectrometry (GC-MS) [2]. Confirmative diagnostic possibilities include direct measurement of mevalonate kinase activities in white blood cells or primary skin fibroblasts [3] from patients, and/or molecular analysis of the MVK gene [8]. 

If a normal person is given an inhibitor for HMG-CoA reductase, cholesterol synthesis is inhibited in the liver. Lower levels of cholesterol then signal the synthesis of increased levels of LDL receptors. This increases the uptake of LDL into the liver and reduces serum LDL. In a patient with FH, this has little effect because there are no LDL receptors. The only effect is that the liver does not make as much cholesterol and does not contribute as much to serum LPT, levels. The new liver will make normal amounts of LDL receptors and have normal uptake of LDL from the blood. This result will dramatically lower serum LDL levels and prevent the new heart from developing coronary artery disease. If the liver transplant had not been done, the heart transplant would have been to no avail. 

Elevated levels of cholesterol in the blood, or hypercholesterolemia, have been linked to heart disease. Cholesterol, a necessary component of all cell membranes, is available to the body by two routes through the diet and through synthesis by the body itself. When changes to one s diet fail to reduce cholesterol levels, medication that inhibits cholesterol biosynthesis may be necessary. The biosynthetic pathway for cholesterol synthesis starts with acetyl-CoA (2.15) (Scheme 2.3). Through a series of steps, three... 

Administration of 2,3,7,8-TCDD to rodents was also shown to reduce blood corticosterone levels (Balk and Piper 1984 DiBartolomeis et al. 1987 Mebus and Piper 1986). This effect has been attributed to decreased corticosterone synthesis by decreasing cholesterol side-chain cleavage in the adrenal gland. More recent studies suggested that 2,3,7,8-TCDD may interfere with secretion or synthesis of appropriate, bioactive ACTH from the anterior pituitary gland, which could compromise adrenal steroidogenenesis (Bestervelt et al. 1993). 

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