Cholesterol synthesis hepatic

The statin family of six closely related hypocholesterolemic drugs are all potent competitive inhibitors of the enzyme 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG CoA reductase), the rate-limiting enzyme in cholesterol biosynthesis. The liver is their target organ, and decreased hepatic cholesterol synthesis ultimately leads to increased removal of LDL particles from the circulation. As a consequence, all other hypocholesterolemic drugs have been relegated to secondary status. 

The answer is d. (Hardman, pp 885-886. Katzung, pp 591-592.) Atorvastatin is a structural analogue of an intermediate formed from the action of HMG-CoA reductase. This could result in a modest decrease in plasma cholesterol. Hepatic cholesterol synthesis may decrease significantly however, nonhepatic tissues increase their rate of synthesis as a compensatory mechanism. The other and perhaps more important effect of the HMG-CoA inhibitors is to increase high-affinity LDL receptors. The plasma LDL is lowered by this action because of an increase in the catabolic rate of LDL and hepatic extraction of LDL precursors. 

The HMG-CoA reductase inhibitors (Statins like simvastatin, lovastatin, pravastatin, fluvastatin, etc.) inhibit the enzyme and thereby decrease the hepatic cholesterol synthesis and increase the synthesis of LDL receptors causing increased clearance of LDL and a reduced concentration of LDL cholesterol in plasma. HMG-CoA reductase inhibitors are used to treat elevated LDL which also causes a small reduction in plasma triglycerides and an increase in HDL cholesterol. 

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-... 

Intravenous administration of 7-ketocholesterol decreased the uptake of cholesterol into rabbit aorta.75 5a-Cholest-8(14)-en-38-ol-15-one suppressed serum cholesterol levels and hepatic cholesterol synthesis. 6 S-8527 significantly reduced serum cholesterol by inhibiting the hepatic synthesis of lipoprotein fractions carrying cholesterol.77 Metformin produced only a slight reduction of plasma cholesterol levels in rabbits fed a high cholesterol diet. However, it markedly decreased aortic cholesterol esters and the atheromatous process, with a simultaneous change in the composition of VLDL.78 79... 

HMG-CoA reductase inhibitors (statins) inhibit the regulatory step in the biosynthesis of cholesterol. They lower serum cholesterol and LDL cholesterol by inhibition of hepatic cholesterol synthesis and, more importantly, by up-regulating LDLreceptor activity. 

Thus, carbon disulfide does affect liver enzymes, particularly those related to lipid metabolism. The increases in serum cholesterol that are sometimes seen following carbon disulfide exposure may be a result of increased hepatic cholesterol synthesis. 

Fig. 13. The relationship between the appearance rate of newly synthesized cholesterol in mesenteric lymph and the rate of hepatic cholesterol synthesis in the same animal. These studies were carried out as described in the legend to Fig. 12 but contained an additional group of animals that were fed different amounts of cholesterol to alter rates of hepatic cholesterol synthesis.

In mammals, cholesterol is carried via the plasma in each of the major lipoprotein classes, namely chylomicrons, very-low-density lipoproteins (VLDL), low-density lipoproteins (LDL) and high-density lipoproteins (HDL) [111-120] (cf. Chapters 2 and 4). Cholesterol delivered to the liver in the chylomicron remnant is mainly derived from the diet or from the novo synthesis in the intestine and so represents a net increase in cholesterol entering into the body and results in an appropriate compensatory suppression of hepatic cholesterol synthesis. 

Several sources of cellular cholesterol contribute to RCT. Part of the process of RCT reflects peripheral (extra-hepatic) cholesterol synthesis. Despite the down-regulation of cholesterol synthesis mediated by the LDL receptor via the delivery of LDL, a considerable amount of sterol is made in peripheral tissues. The importance of this source of cholesterol to homeostasis may be as great as that of dietary cholesterol in many individuals. After hydrolysis of LDL-CE by cellular cholesterol esterases, this cholesterol is made available for recycling to the cell surface and can be recovered there by apo A1 for incorporation into HDLs. Cholesterol is also available from VLDLs, LDLs, and chylomicrons directly internalized by peripheral cells. Cholesterol from HDLs bypasses the lysosomal pathway and becomes part of recycling endosomes that return to the cell surface. Some of the cholesterol recovered on HDLs originates from blood cells. Finally, some cholesterol is transferred directly to other lipoproteins from chylomicrons, VLDLs, and LDLs, without entering the cell. 

Lovastatin (Mevacor ) (3), simvastatin (Zocor ) (15), pravastatin (Pravachol ) (19), atorvastatin (Lipitor ) (20), cerivastatin (Baycol , withdrawn on August 1, 2003) (21), and fluvastatin (Lescol ) (22) were introduced to lower total cholesterol levels, and especially LDL-cholesterol levels to prevent coronary heart disease. These HMG-CoA inhibitors inhibit de novo synthesis of cholesterol in the liver. The rate-limiting enzyme in cholesterol synthesis is HMG-CoA reductase, which catalyzes the conversion of HMG-CoA to mevalonate. The resulting decrease in hepatic cholesterol synthesis leads to increased synthesis of... 

When food supplies are plentiful, hormonal activation leads to fatty acid, triacylglycerol, and cholesterol synthesis. A high dietary intake and intestinal absorption of cholesterol will compensatorily reduce the rate of hepatic cholesterol synthesis, in which case the liver acts as a recycling depot for sending excess dietary cholesterol to the peripheral tissue when needed as well as accepting cholesterol from these tissues when required. The pathways of cholesterol metabolism were discussed in Chapter 34. 

Drugs Drug therapy can reduce fat absorption from the intestine (resins), modify hepatic cholesterol synthesis (HMG-CoA reductase inhibitors), decrease secretion of lipoproteins (niacin), increase peripheral clearance of lipoproteins (fibrates). and can perhaps exert other effects. These drugs are all given orally (Figure 35-1). 

In the preceding section of the paper, it was suggested that cholesterol biosynthesis is reduced, and serum cholesterol level is lowered, where the reaction in which HMG-CoA is converted to mevalonic acid is suppressed by HMGR inhibitory agents. Here we propose a new concept, namely, that the rate of hepatic cholesterol synthesis can fluctuate and can, in turn, cause variations in serum cholesterol levels of individuals. We believe such incidences can occur when variations in circadian rhythmicity of the hormones insulin and glucagon can cause biodynamic interconversion between the active (dephosphorylated) and the inactive (phosporylated) species of HMGR. We will try to explain this new idea in terms of circadian rhythmicity of cholesterol biosynthesis, and develop an interrelationship between fluctuations in cholesterol biosynthesis, stress, and cardiovascular health. 

Introduction of the statins in the mid-1980s transformed cholesterol management [38]. Isolated from the culture broths of penicilhns in the 1970s, they proved to be specific, competitive inhibitors of HMG CoA reductase (3-hydoxy 3-methylglutaryl coenzyme A reductase). This enzyme converts HMG CoA into mevalonate, the first committed step in cholesterol synthesis and an important site of metabolic control. The reduction in hepatic cholesterol synthesis (approximately 40% in vivo) results in up-regulation of LDL receptor activity with binding and uptake of plasma LDL to restore hepatic cholesterol balance. The activity of the LDL receptor is a major determinant of plasma cholesterol levels. These mechanisms are now well understood at a molecular level. 

Serum cholesterol is usually markedly elevated in biliary obstruction, with especially high values in biliary cirrhosis. A positive correlation is found occasionally (196) but not constantly (193) between the serum bile acid and cholesterol levels. An absence of bile acids in the gut lumen and a reduced cholesterol absorption may stimulate, at least initially, both intestinal and hepatic cholesterol production cf. 92,223), and this in association with a block in elimination both as bile acids and as cholesterol itself rapidly raises the serum cholesterol level. However, in biliary obstruction of long duration, e.g., in biliary cirrhosis, sterol balance studies and urinary bile acid measurement indicate that cholesterol synthesis is markedly reduced (88). In parenchymal cell damage of the liver, the serum cholesterol is normal or decreased, probably because the hepatic cholesterol synthesis, due to cell injury, is reduced in proportion to, or proportionally more than, the decreased cholesterol elimination (11,182) and, furthermore, intestinal and hepatic cholesterogenesis may still be under the partial feedback control of bile acids and absorbed cholesterol, respectively. 

Rowachol has been shown to inhibit hepatic cholesterol synthesis mediated by a decreased hepatic 5-3-hydroxy-3-methylgutaryl-CoA reductase activity (Middleton and Hui, 1982) the components mostly responsible for this activity were menthol and 1,8-cineole, with pinene and camphene having no signi cant effect (Clegg et ah, 1980). A reduction in cholesterol crystal formation in the bile of gallstone patients has been demonstrated in a small trial using Rowachol (von Bergmann, 1987). 

Clegg, R. J., Middleton, B., Bell, G. D., White, D. A. 1980. Inhibition of hepatic cholesterol synthesis and S-3-hydroxy-3-methylglutaryl-CoA reductase by mono and bicyclic monoterpenes administered in vivo. 

Bochenek, W., and Rodgers, J. B., 1978, Effects of saturated and unsaturated fats given with and without dietary cholesterol on hepatic cholesterol synthesis and hepatic lipid metabolism, Biochim. Biophys. Acta 528 1. 

ScHADE, H., and P. Saltman Influence of nicotinic acid on hepatic cholesterol synthesis in rabbits. Proc. Soc. exp. Biol. (N. Y.) 102, 265 (1959). 

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