Cholesterol synthesis inhibition

Especially the hybrid hamster strain Bio FiB (Bio Breeders Fitchburg, MA, USA) is more susceptible to dietary induced atherosclerosis than other strains (Kowala et al. 1991). Early atherosclerotic lesions can be induced within a 3-months-feeding of a cholesterol/butter-enriched diet. In these animals simvastin dose-dependently inhibited the development of hyperlipidemia and the plaque formation by cholesterol synthesis inhibition The histopathological examination of the aortas showed that the choles-terol/butter fed FiB hamster developed atherosclerotic lesions and functional changes in the aorta which are closely related to man (Schafer et al. 1999). 

C. Reduction of HMG CoA to mevalonic acid is an early step in cholesterol synthesis. Inhibition of this step would lead to an increase in cellular levels of HMG CoA and a decrease in squalene, an intermediate beyond this step, and cholesterol. The decreased cholesterol levels in cells cause ACAT activity to decrease and synthesis of LDL receptors to increase. Because the receptors function (but at a less than normal rate), more receptors cause more LDL to be taken up from the blood. Consequently, blood cholesterol levels decrease, but blood triacylglyc-erol levels do not change much, since LDL does not contain much triacylglycerol. 

Curran GL, Azarnoee DL and Bolinger RF (1959) Effect of cholesterol synthesis inhibition in normocholesteremic young men. J Clin Invest 38 1251-1261. 

Cholesterol synthesis inhibition leads to cell proUferation inhibition provided the cell has no alternative source of cholesterol, which is easily achieved in vitro by incubating the cells in the absence of Upoprotein in the medium (Vitols et al. 1994). In LDL-receptor deficient cells, the effect of cholesterol synthesis inhibition on cell growth is not prevented by adding LDL to the medium, illustrating the role of LDL receptor in the provision of cholesterol for cell proUferation (Cuthbert et al. 1986, MartInez-Botas etal. 1999). Lovastatin blocked HL-60 cell proUferation (MartInez-... 

Effect of cholesterol synthesis inhibition in normocholesteremic young men. 

Saponins. Although the hypocholesterolemic activity of saponins has been known since the 1950s, thek low potency and difficult purification sparked Htde interest in natural saponins as hypolipidemic agents. Synthetic steroids (292, 293) that are structurally related to saponins have been shown to lower plasma cholesterol in a variety of different species (252). Steroid (292) is designated CP-88,818 [99759-19-0]. The hypocholesterolemic agent CP-148,623 [150332-35-7] (293) is not absorbed into the systemic ckculation and does not inhibit enzymes involved in cholesterol synthesis, release, or uptake. Rather, (293) specifically inhibits cholesterol absorption into the intestinal mucosa (253). As of late 1996, CP-148,623 is in clinical trials as an agent that lowers blood concentrations of cholesterol (254). 

The primary transporter of cholesterol in the blood is low density Hpoprotein (LDL). Once transported intraceUularly, cholesterol homeostasis is controlled primarily by suppressing cholesterol synthesis through inhibition of P-hydroxy-P-methyl gluterate-coenzyme A (HMG—CoA) reductase, acyl CoA—acyl transferase (ACAT), and down-regulation of LDL receptors. An important dmg in the regulation of cholesterol metaboHsm is lovastatin, also known as mevinolin, MK-803, and Mevacor, which is an HMG—CoA reductase inhibitor (Table 5). 

HMG-CoA-Reductase Inhibitors. Figure 1 Mechanism of action of statins - cholesterol synthesis pathway. The conversion of acetyl CoA to cholesterol in the liver. The step of cholesterol biosynthesis inhibited by HMG-CoA reductase inhibitors (statins) is shown. 

LDL (apo B-lOO, E) receptors occur on the cell surface in pits that are coated on the cytosolic side of the cell membrane with a protein called clathrin. The glycoprotein receptor spans the membrane, the B-lOO binding region being at the exposed amino terminal end. After binding, LDL is taken up intact by endocytosis. The apoprotein and cholesteryl ester are then hydrolyzed in the lysosomes, and cholesterol is translocated into the cell. The receptors are recycled to the cell surface. This influx of cholesterol inhibits in a coordinated manner HMG-CoA synthase, HMG-CoA reductase, and, therefore, cholesterol synthesis stimulates ACAT activ-... 

Hu, X.M. et al.. Inhibition of growth and cholesterol synthesis in breast cancer cells by oxidation products of beta-carotene, J. Nutr. Biochem., 9, 567, 1998. 

Starvation elicits mobilization of triglycerides from the adipose tissue and inhibits the endogenic cholesterol synthesis owing to the low activity of hydroxy-methylglutaryl-CoA reductase. The latter process provides the possibility for the active production of ketone bodies in the liver. 

A 47-year-old male is seen in the medicine clinic with recently diagnosed mixed hyperlipidemia. An anti hyp er lip idem ic is administered that favorably affects levels of VLDL, low-density lipoprotein (LDL), and high-density lipoprotein (IIDL) and inhibits cholesterol synthesis. This drug is ... 

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. 

Combination therapy with a statin and BAR is rational because numbers of LDL-Rs are increased, leadingto greater degradation of LDL cholesterol intracellular synthesis of cholesterol is inhibited and enterohepatic recycling of bile acids is interrupted. 

In isolated mouse nerves, the synthesis of all lipids is reduced after mercuric chloride, but the cholesterol synthesis is inhibited most strongly [ 123], It has been suggested that these lipid alterations might participate in the pathogenesis of membrane damage and cell death. 

The therapeutic class that uniquely exemplifies lactone prodrugs are the statins, i.e., the cholesterol-lowering agents that act by inhibiting 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase (EC 1.1.1.34). This microsomal enzyme catalyzes conversion of HMG-CoA to mevalonate, an important rate-limiting step in cholesterol biosynthesis. Cholesterol synthesis occurs mainly... 

An enzyme (see Section 2.6) called HMG-CoA reductase is involved in the biosynthesis of cholesterol. Drugs such as atorvastatin (Lipitor) and simvastatin (Zocor) are competitive inhibitors of HMG-CoA reductase. They inhibit cholesterol synthesis by increasing the number of LDL receptors to take up the LDL. 

Warfarin CoA to mevalonic acid for the synthesis of cholesterol Anticoagulant Inhibits synthesis of clotting factors II (prothrombin), VII, IX,... 

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 health impairing and toxic elfects of oxidation of lipids are due to loss of vitamins, polyenoic fatty acids, and other nutritionally essential components formation of radicals, hydroperoxides, aldehydes, epoxides, dimers, and polymers and participation of the secondary products in initiation of oxidation of proteins and in the Maillard reaction. Dilferent oxysterols have been shown in vitro and in vivo to have atherogenic, mutagenic, carcinogenic, angiotoxic, and cytotoxic properties, as well as the ability to inhibit cholesterol synthesis (Tai et ah, 1999 Wpsowicz, 2002). 

The protein p21 can be induced by p53-independent factors, including drugs known as statins. These drugs are used to lower blood cholesterol by inhibition of its synthesis, via the enzyme HMG-CoA reductase. It is not known how statins affect the p21 protein. 

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. 

Figure 22.10 Reverse cholesterol transfer. High density lipoprotein (HDL) collects cholesterol from cells in various tissues/ organs the complex is then transported in the blood to the liver where it binds to a receptor on the hepatocyte, is internalised and the cholesterolis released into the hepatocyte. This increases the concentration in the liver cells which then decreases the synthesis of cholesterol by inhibition of the rate-limiting enzyme in cholesterol synthesis, HMG-CoA synthase. The cholesterol is also secreted into the bile or converted to bile acids which are also secreted into the bile, some of which is lost in the faeces (Chapter A).

Ezetimibe has a mechanism of action that differs from those of other classes of cholesterol-reducing compounds. Ezetimibe does not inhibit cholesterol synthesis in the liver or increase bile acid excretion. 

Cholesterol metabolism. Hydrogenated oil, administered orally to hamsters at a dose of 20% of diet for 4 weeks, induced hypercholesterolemia. Oil feeding had no effect on cholesterol synthesis but markedly inhibited cholesterol esterification in both the liver and the intestine. The diet-induced hypercholesterolemia was strongly correlated with an increase in acyl-CoA/cholesterol acyltransferase activity. The hypercholesterolemia increased aortic uptake of cholesterol and hence acyl-CoA/cholesterol acyltransferase activity " Coconut fat, administered orally to rabbits with partial ileal bypass, produced a significant increase of serum total cholesterol and phospholipids concentrations. The effect on semm lipids of the type of fat was similar in control and partial ileal bypass rabbits A Coconut—a main source of energy for two... 

Mechanism of Action An antihyperlipidemic that inhibits hydroxymethylglutaryl-CoA (HMG CoA) reductase, the enzyme that catalyzes the early step in cholesterol synthesis. Therapeutic Effect Decreases LDL and VLDL cholesterol, and plasma triglyceride levels increases HDL cholesterol concentration. 

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