Primary bile acids synthesis

Hvdroxvlation pathway An alternative explanation for the bile acid synthetic defect in CTX has been proposed by Oftebro and colleagues which starts via 26-hydroxylation of 5P-cholestane-3a,7a,12a-triol (IX, Fig. lOa and 10b). In this pathway the mitochondrial fraction of both human and rat liver contains a 26-hydroxylase enzyme (63) which can convert 5P-cholestane-3a,7a,12a-triol (IX ) to 5P-cholestane-3a,7a,12a,26-tetrol (XI) (Fig. 10a and 10b ). This tetrol is oxidized to 3a,7a,12a-trihydroxy-5P-cholestan-26-oic acid (THCA, XII) by liver cytosol (2,64). Further hydroxylation at C-24 forms varanic acid (XIV) and its side chain is shortened with oxidation at C-24 to yield cholic acid (X,Fig. 10 a). These investigators demonstrated diminished mitochondrial 26-hydroxylation of 5p-cholestane-3a,7a,12a-triol and 5P-cholestane-3a,7a-diol, possible precursors for cholic acid and chenodeoxycholec acid in CTX liver. As a consequence, neither 26-hydroxylated intermediates can be formed so that total primary bile acid synthesis would be diminished. Accordingly, the accumulation of 5P-cholestane-3a,7a,12a,25-tetrol arises from 25-hydroxylation of 5P-cholestane-3a,7a,12a-triol by the alternative microsomal 25-hydroxylation mechanism. 

Assays have also made use of 7a-hydroxysteroid dehydrogenase that can measure the primary bile acids, or for more specialised purposes such as differentiating between pathways of bile-acid synthesis to determine the proportion derived from the acid pathway. 

Intestinal bacteria produce enzymes that can chemically alter the bile salts (4). The acid amide bond in the bile salts is cleaved, and dehydroxylation at C-7 yields the corresponding secondary bile acids from the primary bile acids (5). Most of the intestinal bile acids are resorbed again in the ileum (6) and returned to the liver via the portal vein (en-terohepatic circulation). In the liver, the secondary bile acids give rise to primary bile acids again, from which bile salts are again produced. Of the 15-30g bile salts that are released with the bile per day, only around 0.5g therefore appears in the feces. This approximately corresponds to the amount of daily de novo synthesis of cholesterol. 

Bile salts secreted into the intestine are efficiently reabsorbed (greater than 95 percent) and reused. The mixture of primary and secondary bile acids and bile salts is absorbed primarily in the ileum. They are actively transported from the intestinal mucosal cells into the portal blood, and are efficiently removed by the liver parenchymal cells. [Note Bile acids are hydrophobic and require a carrier in the portal blood. Albumin carries them in a noncovalent complex, just as it transports fatty acids in blood (see p. 179).] The liver converts both primary and secondary bile acids into bile salts by conjugation with glycine or taurine, and secretes them into the bile. The continuous process of secretion of bile salts into the bile, their passage through the duodenum where some are converted to bile acids, and their subsequent return to the liver as a mixture of bile acids and salts is termed the enterohepatic circulation (see Figure 18.11). Between 15 and 30 g of bile salts are secreted from the liver into the duodenum each day, yet only about 0.5 g is lost daily in the feces. Approximately 0.5 g per day is synthesized from cholesterol in the liver to replace the lost bile acids. Bile acid sequestrants, such as cholestyramine,2 bind bile acids in the gut, prevent their reabsorption, and so promote their excretion. They are used in the treatment of hypercholesterolemia because the removal of bile acids relieves the inhibition on bile acid synthesis in the liver, thereby diverting additional cholesterol into that pathway. [Note Dietary fiber also binds bile acids and increases their excretion.]... 

Figure 6.2 Synthesis of primary bile acids from cholesterol. 

A. The enzyme sterol 27-hydroxylase catalyzes the hydroxylation of carbon 27 of the steroid side chain in the conversion of cholesterol to the primary bile acids. It is a mitochondrial, cytochrome P450 enzyme that has a broad specificity and can act on cholesterol as well as its reduced and hydroxylated metabolites. A deficiency in this enzyme leads to decreased bile acid synthesis and increased conversion of cholesterol to cholestanol. 

Zollner, G., Wagner, M., Fickert, P., Silbert, D., Gumhold, J., Zatloukal, K., Denk, H., and Trauner, M. (2007) Expression of bile acid synthesis and detoxification enzymes and the alternative bile acid efflux pump MRP4 in patients with primary biliary cirrhosis. 

FH represents only about 2% of HPCs. All others, although likely to involve some genetic factors, have a major dietary component. It is now understood that any increased liver cholesterol levels will decrease LDL receptor synthesis by a biofeedback mechanism. Therefore, any reason for elevated cholesterol levels such as increased absorption or decreased bile acid synthesis can lead to primary HPC not of the familial type. In addition, reduced receptor activity may complicate the picture, either because there are fewer of them or they function less efficiently (e.g., lowered LDL affinity). Drug therapy is potentially useful in such patients. 

The pathways for primary bile salt synthesis shown in Fig. 2 are derived from studies in man (3-7) and are believed to represent the major synthetic routes. Several of the intermediates shown in Fig. 2 have been isolated from human bile. Trihydroxycoprostanic acid, XV, has been crystallized from human fistula bile (8) and shown to be derived from cholesterol (4,5). The major metabolite of trihydroxycoprostanic acid in man is cholic acid (5). 5/5-Cholestane-3a,7a-diol, X, has been identified as a product of cholesterol oxidation (6) and 3a,7a-dihydroxycoprostanic acid, XI, has been isolated from human fistula bile (7). 

Fig. 2. Possible pathways for primary bile salt synthesis in man compiled from various sources (see text). V, Cholesterol VI, cholest-5-ene-3i3,7a-diol VII, 7a-hydroxycholest-4-en-3-one VIII, 7a-hydroxy-5/S-cholestan-3-one IX, 5/3-cholestane-3a,7a-diol X, 3a,7a-dihydroxy-5/3-cholestanoic acid XI, 3a,7a-dihydroxy-5/5-cholanoic acid (chenodeoxycholic acid) XII, 7a,12a-dihydroxy-cholest-4-en-3-one XIII, 7a,12a-dihydroxy-5/3-cholestan-3-one XIV, 5 -cholestane-3a,7a,12a-triol XV, 3a,7a,12a-trihydroxy-5/5-cholestanoic acid XV, 3a,7a,12a-trihydroxy-5/3-cholanoic acid XVI, 3a,7a,12a-trihydroxy-5/3-cholanoic acid (cholic acid).

Bile acids have two major functions in man (a) they form a catabolic pathway of cholesterol metabolism, and (b) they play an essential role in intestinal absorption of fat, cholesterol, and fat-soluble vitamins. These functions may be so vital that a genetic mutant with absence of bile acids, if at all developed, is obviously incapable of life, and therefore this type of inborn error of metabolism is not yet known clinically. A slightly decreased bile acid production, i.e., reduced cholesterol catabolism, as a primary phenomenon can lead to hypercholesterolemia without fat malabsorption, as has been suggested to be the case in familial hypercholesterolemia. A relative defect in bile salt production may lead to gallstone formation. A more severe defect in bile acid synthesis and biliary excretion found secondarily in liver disease causes fat malabsorption. This may be associated with hypercholesterolemia according to whether the bile salt deficiency is due to decreased function of parenchymal cells, as in liver cirrhosis, or whether the biliary excretory function is predominantly disturbed, as in biliary cirrhosis or extrahepatic biliary occlusion. Finally, an augmented cholesterol production in obesity is partially balanced by increased cholesterol catabolism via bile acids, while interruption of the enterohepatic circulation by ileal dysfunction or cholestyramine leads to intestinal bile salt deficiency despite an up to twentyfold increase in bile salt synthesis, to fat malabsorption, and to a fall in serum cholesterol. 

It seems evident that (1) if bile acid elimination is inhibited or impaired as a primary phenomenon, e.g., in biliary obstruction and hypercholesterolemia, a decreased catabolism of cholesterol leads to hypercholesterolemia and reduced cholesterol synthesis (2) if bile acid elimination is primarily augmented, e.g., after an external bile fistula, ileal bypass, ileal resection, cholestyramine treatment, or perhaps a diet rich in fibrous material, conversion of cholesterol to bile acids is enhanced, leading almost always, despite stimulated cholesterol synthesis, to a fall in serum cholesterol (3) if endogenous cholesterol production is primarily increased, e.g., by obesity and excess of calories, bile acid synthesis and elimination are augmented, preventing together with increased neutral sterol elimination in some but not all cases the increase of serum cholesterol. This suggests that removal, not production, of cholesterol is the primary factor which determines serum cholesterol level. 

Since it is quite apparent that augmented bile acid synthesis is a primary phenomenon which leads to increased fecal bile acid excretion in obesity, the bile acid pool should also be large. Unfortunately, measurement of pool size has not yet been performed in relation to body weight or obesity. Enhanced bile acid production in obesity seems not to be an irreversible phenomenon. Thus weight reduction in a few overweight patients brought cholesterol synthesis and also bile acid production down to almost normal limits (136 see Fig. 2). 

Bile acids are formed from cholesterol in the liver via a sequence of reactions initiated by 7a-hydroxylase. Two primary bile acids, cholic acid and chenodeoxycholic acid, are formed and secreted as glycine or taurine conjugates into the bile and intestine. Most of them are reabsorbed, taken up by the liver and resecreted, completing enterohepatic circulation of bile salts. During each cycle a small amount of bile acids escape into the colon and feces and is regenerated by new hepatic synthesis. 

Bile acid synthesis can also be measured isotopically. Of these procedures Lindstedt s method is widely used because it permits the measurement of the pool size, turnover and synthesis rates of the two primary bile acids separately provided that the two differently labeled bile acids are administered and that the H-label is tightly bound and is not subjected to losses due to tritium exchange. The method may not be valid in gross bile acid malabsorption due to incomplete mixing of the labels within the bile acid pool. Comparison of the quantitative data obtained with this and GLC methods have given similar and even markedly different results (cf. 7). Usually the values of the isotopic procedure are somewhat higher than those of the GLC method, a discrepancy which has no explanation at the moment even when the nonspecific losses of tritium is taken into consideration. Hypertriglyceridemic subjects in particular produce much more bile acids on the basis of the isotopic than chemical balance. 

The biliary cholesterol specific activities (after administration of C H]-mevalonic acid) were the same in all groups, but biliary bile acid specific activity was higher in the control baboons than in test animals. These data, plus the higher primary/ secondary bile acid ratio observed in the test animals, suggest that reduced bile acid synthesis may be one cause of the hypercholesteremia observed in animals fed the semi-synthetic diets. 

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... 

Another example in which literature results were reanalyzed in view of the PSSC concept concerns the development of ligands for the farnesoid X receptor. The farnesoid X receptor is a transcriptional sensor for bile acids, the primary products of cholesterol metabolism, and plays an important role in lipid homeostasis. The farnesoid X receptor was, until recently, an orphan receptor, which means that no specific ligands existed for this receptor. Selective ligands for this receptor have been found in natural product libraries described by Nicolaou et al. The group of Nicolaou developed solid phase synthesis methods to make combinatorial libraries based on a benzopyran core structure. " A 10,000-membered combinatorial library based on the benzopyran core structure was synthesized and screened for activity on the farnesoid X receptor. The first specific ligands for the... 

We first describe the biosynthesis of fatty acids, the primary components of both triacylglycerols and phospholipids, then examine the assembly of fatty acids into triacylglycerols and the simpler membrane phospholipids. Finally, we consider the synthesis of cholesterol, a component of some membranes and the precursor of steroids such as the bile acids, sex hormones, and adrenocortical hormones. 

The primary mechanism by which lecithin lowers cholesterol is by decreasing the absorption of dietary cholesterol from the intestine to the blood stream (269, 270). There is also evidence that lecithin intake lowers cholesterol by increasing the amount of cholesterol used in the production of bile salts (271). As more cholesterol is used for bile salt synthesis, less is available to reach the blood stream and damage blood vessels. Lecithin also contributes polyunsaturated fatty acids to the diet, which may help control blood cholesterol levels. 

Although the mitochondria are the primary site of oxidation for dietary and storage fats, the peroxisomal oxidation pathway is responsible for the oxidation of very long-chain fatty acids, jS-methyl branched fatty acids, and bile acid precursors. The peroxisomal pathway also plays a role in the oxidation of dicarboxylic acids. In addition, it plays a role in isoprenoid biosynthesis and amino acid metabolism. Peroxisomes are also involved in bile acid biosynthesis, a part of plasmalogen synthesis and glyoxylate transamination. Furthermore, the literature indicates that peroxisomes participate in cholesterol biosynthesis, hydrogen peroxide-based cellular respiration, purine, fatty acid, long-chain... 

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