Metabolism of cholesterol

Cholesterol is involved in two major biological processes. It is a structural component of cell membranes (Chap. 6) and the parent compound from which steroid hormones, vitamin D3 (cholecalciferol), and the bile salts are derived. Cholesterol is synthesized de novo in the liver and intestinal epithelial cells and is also derived from dietary lipid. De novo synthesis of cholesterol is regulated by the amount of cholesterol and triglyceride in the dietary lipid. 

The biosynthesis of cholesterol begins with acetyl-CoA in what is a very complex process involving 32 different enzymes, some of which are soluble in the cytosol and others of which are bound to the ER membrane. The basic carbon building block of cholesterol is isoprene (Chap. 6). 

In the initial reactions of the biosynthetic pathway, 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) is formed from acetyl-CoA by the action of thiolase and HMG-CoA synthase in the cytosol of the liver cell. 

Question By what biochemical means is 3-hydroxy-3-methylglutaryl-CoA reduced to the isoprene compound, isopentenyl pyrophosphate  

NADPH is the electron donor in a reaction catalyzed by hydroxymethylglutaryl-CoA reductase, followed by two phosphorylation reactions involving ATP and two specific kinases, and an ATP-dependent decarboxylation. The process is summarized in Example 13.15 and Fig. 13-21. 

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To explain the relationship between Lp(a) concentrations and risk of atherosclerosis, several hypothesis could be brought forward first, Lp(a) affects the metabolism of cholesterol and LDL secondly, Lp(a) plays a role in foam-cell and plaque formation thirdly, Lp(a) interacts with the activation of plasminogen to plasmin, the key step in the fibrinolytic system (L10, M27). Such activation can occur in two different localizations, i.e., on fibrin and its proteolytic residues, and on the surface of endothelial and monocytic cells. 

In the animal body three important groups of hormones are formed by the metabolism of cholesterol the progestins, the sex hormones, and the adrenal cortical hormones 249 Their synthesis occurs principally in mitochondria of the adrenal cortex and the gonads. Steroid hormone synthesis is regulated by hormones, such as corticotropin (ACTH), from the anterior pituitary250 (see Chapter 30) and is also dependent upon the recently discovered steroidogenic acute regulatory protein, which in some way promotes the movement of stored cholesterol into mitochondrial membranes.251 252 Some major pathways of... 

Structure and Functions of Biological Membranes 381 Metabolism of Fatty Acids 411 Biosynthesis of Membrane Lipids 436 Metabolism of Cholesterol 459... 

The metabolism of cholesterol in mammals is extremely complex. A summary sketch (fig. 20.24) helps to draw the major metabolic interrelationships together. Cholesterol is biosynthesized from acetate largely in the liver (fig. 20.24a) or taken in through the diet (fig. 20.24b). From the intestine, dietary cholesterol is secreted into the plasma mainly as a component of chylomicrons. The triacylglycerol components of chylomicrons are quickly degraded by lipoprotein lipase, and the remnant particles are removed by the liver. Apoproteins and lipid components of the chylomicrons and remnants appear to exchange with HDL. Cholesterol made in the liver (fig. 20.24a) has several alternative fates. It can be (1) secreted into plasma as a component of VLDL,... 

In this chapter we dealt primarily with the metabolism of cholesterol, the most prominent member of the steroid family of lipids, and with the associated plasma lipoproteins. The chief points in our discussion are as follows ... 

The final chapter in part 5, chapter 20, Metabolism of Cholesterol, deals with the synthesis of cholesterol and some of its derivatives, the steroid hormones and the bile acids. This chapter considers the structure, function and metabolism of these molecules. Also, the health-related concerns associated with cholesterol excess are addressed. 

Ikeda, I., Morioka, H., and Sugano, M. 1979. The effect of dietary -sitosterol and /Tsitostanol on the metabolism of cholesterol in rats. Agric. Biol. Chem. 43, 1927-1933. 

Kesaniemi, Y.A. and Grundy, S.M. 1986. Effects of dietary polyenylphosphatidylcholine on metabolism of cholesterol and triglycerides in hypertriglyceridemic patients. Am. J. Clin. Nutr. 43, 98-107. 

Sterol carrier protein 2 has also been shown to be involved in the intracellular transport and metabolism of cholesterol. Hirai et al. (1994) suggested that sterol carrier protein 2 plays an important role during foam cell formation induced by acetylated LDL and may be an important step in atherosclerosis [142], Lipoproteins can bind lipopolysaccharide and decrease the lipopoly-saccharide-stimulated production of proinflammatory cytokines [142, 143], In addition, lipoprotein entrapment by the extracellular matrix can lead to the progressive oxidation of LDL because of the action of lipoxygenases, reactive oxygen species, peroxynitrite, or myeloperoxidase [144, 145],... 

The bile acids are produced in the liver by the metabolism of cholesterol. They are di- and trihydroxylated steroids with 24 C atoms. The structure of cholic acid was seen earlier (Sec. 6.6). Deoxycholic acid and chenodeoxycholic acid are two other bile acids. In the bile acids, all the hydroxyl groups have an a orientation, while the two methyl groups are /3. Thus, one side of the molecule is more polar than the other. However, the molecules are not planar but bent because of the cis conformation of the A and B rings. 

The metabolism of cholesterol involves modifications to the alkyl side chain and the introduction of substituents onto the phenanthrene ring. A group of enzymes, monooxygenases, plays an important role in catalyzing the formation of bile salts in the liver and steroid hormones in the adrenal gland... 

Synthesis and metabolism of cholesterol, phospholipids, triglycerides and lipoproteins. 

It is known that apoE plays an important role in the distribution and metabolism of cholesterol and triglycerides within many organs and cell types in the human body (Mahley et al., 2006). The apoE polymorphism is unique to humans and has been... 

The circulating level of cholesterol has been established as a risk factor in the development of atherosclerosis, resulting in myocardial infarction in humans. The metabolism of cholesterol involves a set of apolipoproteins involved in transporting cholesterol in vesicular complexes and the low-density lipoprotein (LDL) receptors on cells (Brown and Goldstein, 1990). 

As in the previous Report/ the biosynthesis of steroids and triterpenoids is divided into three sections. This section considers the biosynthesis of cholesterol and related steroids, such as ergosterol. Further metabolism of cholesterol is reviewed in Section 8, whereas non-steroidal triterpenoids are considered in Section 9. The biosynthesis of steroids in lower organisms and arthropod steroid metabolism are discussed in Section 11. 

Because of its importance in human biology, cholesterol has received enormous attention from researchers. For this reason the metabolism of cholesterol is better understood than that of any other isoprenoid molecule. 

Copper complex modulation of steroid hydroxylations have also been reported [690]. A single dose of Cu(II)sulphate injected into rats caused a 2-to 3-fold increase in adrenal copper, a significant (P < 0.05) increase in mitochondrial P-450-dependent steroid 11-jS-hydroxylase activity, and an 85% increase in concentration of P-450 as well as a 3-fold increase in fi-aminolevuli-nate synthetase, which suggests a positive feedback stimulation of P-450 synthesis. Chronic treatment with Cu(II)sulphate for 7 days caused a decrease in 11-jS-hydroxylase activity (P<0.05) and a decrease in plasma corticosterone concentration (P<0.05) while there was a concomitant increase in cholesterol side-chain cleavage, suggesting the metabolism of cholesterol by some other P-450 following maximal corticosterone synthesis. A positive feedback for 6-aminolevulinate synthesis was also evidenced by an increase in synthetase activity. 

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