Cholesterol bile acid biosynthesis from

During bile acid biosynthesis, modifications to the cyclopentanophen-anthrene (steroid) nucleus are thought to precede the oxidation and cleavage of the cholesterol side chain. The first and rate-controlling step in bile acid synthesis is the 7o-hydroxylation of cholesterol (I) to form 7a-hydroxy-choles-terol (II) (Fig. 3). This step is catalyzed by cholesterol 7a-monooxygenase (cholesterol 7a-hydroxylase) (EC 1.14.13.17), a microsomal enzyme (M37). Further metabolism of 7a-hydroxy-cholesterol involves oxidation of the 3p-hydroxyl group and isomerization of the double bond from C-5,6 to C-4,5,... 

The possibUity of multiple pathways in bile acid biosynthesis in man has been discussed by Vlahcevic et al. [180-182]. A number of labelled 7 -hydroxylated intermediates in bile acid biosynthesis were administered to bile fistula patients as well as patients with an intact enterohepatic circulation. In accordance with previous work with bile fistula rats, the spedfic activity of the isolated chohc add was in general considerably lower than that of chenodeoxychohc acid. On the basis of this finding, it was suggested that a portion of chohc acid was synthesized via a route not involving initial 7a-hydroxylation of cholesterol. It must then be assumed that the administered intermediate mixes with the endogenous pool of the same steroid. However, due to compartmentation, the metabolic fate of a precursor reaching the hepatocyte might be different from that of the the same compound formed within the cell. Normally, the different precursors are present in the cells in trace amounts... 

The possibility that the biosynthesis of bile acids is regulated by a negative feedback mechanism was supported by early experiments by Thompson and Vars [206] and Eriksson [207], who showed that the rate of bile acid synthesis in rats increased about 10-fold when a bile fistula is made. Bergstrom and Danielsson demonstrated that duodenal infusion of taurochenodeoxycholic acid in bile fistula rats restored the increased synthesis to a normal rate [208]. Danielsson et al. [44] showed that the cholesterol 7a-hydroxylase activity increased in parallel with the bile acid synthesis after cannulation of the bile duct in rats. In a subsequent work by Mosbach et al., it was reported that the incorporation of isotope from labelled acetate, mevalonate and cholesterol but not from labelled 7a-hydroxycholesterol into bile acids was inhibited by duodenal infusion of taurocholate to bile fistula rats [209]. The incorporation of isotope from labelled acetate, mevalonate and cholesterol but not from labelled 7a-hydroxycholesterol was stimulated in perfused livers of cholestyramine-treated rabbits [210]. It was concluded that there are essentially no rate-limiting steps beyond 7a-hydroxycholesterol in the biosynthesis of bile acids from acetate. Since both cholesterol and bile acid biosynthesis was subjected to negative feedback inhibition by bile acids, it cannot be excluded that inhibition of cholesterol biosynthesis precedes inhibition of the bile acid biosynthesis, and that the latter inhibition is secondary to the former. 

The possibility that cholesterol 7a-hydroxylase is directly inhibited by bile acids was studied by Mosbach et al. by addition of bile acids or bile salts to microsomal suspension [62]. An inhibition was observed, but this was probably due to non-specific detergent effects. From the time lag observed in the stimulation of bile acid biosynthesis after introduction of a bile fistula, it may be concluded that the effects of the bile acids most probably are mediated by effects on protein synthesis or protein catabolism. 

Figure 2.17 Suggested pathway of cholesterol metabolism in human brain based on the identification of metabolites in CSR The left hand branch constitutes the initial steps of the acidic pathway of bile acid biosynthesis. 26-Hydroxycholesterol may be synthesized in brain via a reaction catalyzed by CYP27A1 or imported into brain from the circulation (Heverin, Meaney, Liitjohann, et al. [60].) Thus, the ultimate product of this pathway 7a-hydroxy-3-oxocholest-4-en-26-oic may be derived from brain synthesized or imported sterols. The right-hand branch of the pathway represents the initial steps of the 24-hydroxylase pathway of bile acid biosynthesis. The initial enzyme CYP46A1 is uniquely expressed in nervous tissue (Lund, Guileyardo, and Russell [61]). (See color insert.)...

The molecular regulation of cellular cholesterol metabolism has been elucidated by Brown and Goldstein [64]. Cholesterol is synthesized in the hver by the enzyme HMG-CoA reductase. Subsequently, it is transformed into bile acid in the liver and secreted to the gall bladder. The statins inhibit HMG-CoA reductase, which is a key rate-limiting enzyme in cholesterol biosynthesis. The effective removal of the bile acid from the bile pool is another viable approach to reduce plasma LDLc. Removal of bile acid from the body results in upregulation of bile acid biosynthesis, which subsequently leads to a corresponding overall drop in plasma cholesterol levels [65]. The biochemical process of cholesterol metabolism is schematically illustrated in Fig. 6. 

The primary action of BARs is to bind bile acids in the intestinal lumen, with a concurrent interruption of enterohepatic circulation of bile acids, which decreases the bile acid pool size and stimulates hepatic synthesis of bile acids from cholesterol. Depletion of the hepatic pool of cholesterol results in an increase in cholesterol biosynthesis and an increase in the... 

Although both LDL and HDL are primarily cholesterol particles, most of the cholesterol measured in the blood is assodated with LDL. The normal role of LDL is to deliver cholesterol to tissues for biosynthesis. When a cell is repairing membrane or dividing, the cholesterol is required for membrane synthesis. Bile acids and salts are made from cholesterol in the liver, and many other tissues require some cholesterol for steroid synthesis. As shown in Figure 1-15-6, about 80% of LDL are picked up by hepatocytes, the remainder by peripheral tissues. ApoB-100 is the only apoprotein on LDL, and endocytosis of LDL is mediated by apoB-100 receptors (LDL receptors) clustered in areas of cell membranes lined with the protdn clathrin. 

Cholesterol is a major constituent of the cell membranes of animal cells (see p. 216). It would be possible for the body to provide its full daily cholesterol requirement (ca. 1 g) by synthesizing it itself However, with a mixed diet, only about half of the cholesterol is derived from endogenous biosynthesis, which takes place in the intestine and skin, and mainly in the liver (about 50%). The rest is taken up from food. Most of the cholesterol is incorporated into the lipid layer of plasma membranes, or converted into bile acids (see p. 314). A very small amount of cholesterol is used for biosynthesis of the steroid hormones (see p. 376). In addition, up to 1 g cholesterol per day is released into the bile and thus excreted. 

We begin with an account of the main steps in the biosynthesis of cholesterol from acetate, then discuss the transport of cholesterol in the blood, its uptake by cells, the normal regulation of cholesterol synthesis, and its regulation in those with defects in cholesterol uptake or transport. We next consider other cellular components derived from cholesterol, such as bile acids and steroid hormones. Finally, an outline of the biosynthetic pathways to some of the many compounds derived from isoprene units, which share early steps with the pathway to cholesterol, illustrates the extraordinary versatility of isoprenoid condensations in biosynthesis. 

Sterols and Cholesterol. Natural sterols are crystalline C76 C1(1 steroid alcohols containing an aliphatic side chain at C17. Sterols were first isolated as lionsaponifiable fractions of lipids from various plant and animal sources and have been identified in almost all types of living organisms. By far, the most common sterol in vertebrates is cholesterol (8). Cholesterol serves two principal functions in mammals. First, cholesterol plays a role in the structure and function of biological membranes.. Secondly, cholesterol serves as a central intermediate in the biosynthesis of many biologically active steroids, including bile acids, corticosteroids, and sex hormones. 

Impairment of bile acid absorption and consequent loss of these acids via excretion presumably causes an increase in hepatic conversion of cholesterol to bile acids. This conversion lowers serum cholesterol, particularly when serum contains high levels of cholesterol derived from dietary intake. However, when fed with a cholesterol-free diet, 10% pectin supplementation stimulated a 3-fold increase in cholesterol biosynthesis (77). Biosynthesis of phospholipids and triglycerides also increased significantly hence, it was suggested that these increases occurred in response to diminished fat absorption occasioned by pectin intake. This compensatory biosynthesis of cholesterol and lipids may account for pectin s inability (in most cases) to lower serum cholesterol levels in animals fed cholesterol-free diets. 

A number of cytochrome P450 enzymes are involved in the conversion of acetate to sterols and bile acids (Figure 9.6). The participation of P450 enzymes in pathways of cholesterol biosynthesis and elimination demonstrate their important role in cholesterol homeostasis. Lanosterol 14a-desmethylase, encoded by CYP51A1, is a pivotal P450 involved in cholesterol biosynthesis. The synthesis of bile acids from... 

HMG-CoA reductase is the rate-limiting step of cholesterol biosynthesis, and is subject to complex regulatory controls. A relatively constant level of cholesterol in the body (150-200 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. Cholesterol from both diet and synthesis is utilised 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. 

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