Bile salts synthesis

Impairment of bile salt synthesis was implicated in ever-olimus-induced hypercholesterolemia (407). 

Both IDL and LDL can be removed from the circulation by the liver, which contains receptors for ApoE (IDL) and ApoB-100 (IDL and LDL). After IDL or LDL interacts with these receptors, they are internalized by the process of receptor-mediated endocytosis. Receptors for ApoB-100 are also present in peripheral tissues, so that clearance of LDL occurs one-half by the liver and one-half by other tissues. In the liver or other cells, LDL is degraded to cholesterol esters and its other component parts. Cholesterol esters are hydrolyzed by an acid lipase and may be used for cellular needs, such as the building of plasma membranes or bile salt synthesis, or they may be stored as such. Esterification of intracellular cholesterol by fatty acids is carried out by acyl-CoA-cholesterol acyltransferase (ACAT). Free cholesterol derived from LDL inhibits the biosynthesis of endogenous cholesterol. B-100 receptors are regulated by endogenous cholesterol levels. The higher the latter, the fewer ApoB-100 receptors are on the cell surface, and the less LDL uptake by cells takes place. 

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. 

The major sites of cholesterol synthesis are the liver and the intestines. Generally, about 1/3 of our cholesterol arises from the diet, while 2/3 is made in the body (Jones, 1997), Most of the cholesterol in the body is manufactured by extra-hepatic tissues. This statement applies to most animals, except for rats and mice, where the liver makes most of the body s cholesterol (Dietschy, 1997). Nearly all the cholesterol synthesized in the liver is used for bile salt synthesis. The high contribution of the intestines to the body s synthesis of cholesterol is due to their large surface area and rapid turnover, as discussed in the section on the crypt and villus in Chapter 2,... 

B. Both pregnenolone and progesterone are intermediates in the synthesis of steroid hormones from cholesterol. 7-Hydroxycholesterol is an intermediate in bile salt synthesis, and aldosterone is a mineralocorticoid produced well beyond the branch point for the synthesis of the adrenal and gonadal steroids. Retinoic acid is derived from vitamin A. 

Cholestyramine and colestipol are bile acid sequestranls that enhance cholesterol loss into the feces, thereby stimulating new bile salt synthesis, which lowers liver cholesterol levels and consequently plasma LDL levels. Their adverse effects are also listed. 

Dowling et al. and Small et al. have studied the effects of controlled interruption of the enterohepatic circulation in monkeys [216-218]. It was shown that the regulation of the bile acid biosynthesis was of all or none type. It was established that the increased bile acid biosynthesis in response to interruption of the enterohepatic circulation was limited and reached a maximum rate at only 20% interruption. Up to this level, the increased bile salt loss was compensated for by increased synthesis loss so that bile salt secretion and pool size were maintained at normal levels. With diversion of 37% or more, there was no further increase in hepatic bile salt synthesis to compensate for external loss, and a reduction in bile acid pool size and steathorrhoea were observed. 

Fig. 34.9. The reaction catalyzed by 7a-hydroxylase. An a-hydroxyl group is formed at position 7 of cholesterol. This reaction, which is inhibited by bile salts, is the rate-limiting step in bile salt synthesis.

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).

The rate of cholate synthesis in man is about 200-300 mg/day, as measured by isotope dilution studies. The chenodeoxycholate synthesis rate is similar, so that the total primary bile salt synthesis is about 400-600 mg daily for a healthy adult, and when in the steady state this amount is also the daily fecal excretion rate (12). 

Patients with hypercholesterolemia do not appear to have significant alterations in bile salt synthesis rates, but patients with combined hypercholesterolemia and hypertriglyceridemia have increased synthesis rates for both cholate and chenodeoxycholate (20). Bile salt synthesis rates are not appreciably changed when nicotinic acid feeding lowers plasma cholesterol concentrations (20). Synthesis rates may also be affected by thyroid hormones. Cholic acid synthesis is decreased and half-life prolonged in hypothyroid subjects. These alterations may be corrected with thyroid hormone (21). Bile acid synthesis is increased in thyrotoxicosis (21). 

Calcification of the biliary tree with cholestyramine feeding has been reported (93,96). Gallstone formation has been induced (97) and prevented (98) with cholestyramine in animals. The effects of cholestyramine on bile salt synthesis are discussed in a preceding section. 

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. 

CYP7A1 is critical in bile salts synthesis and cholesterol homeostasis. Imbalances in the level of these two enzymes can cause abnormal liver function. 

Lenicek M, Komarek V, Zimolova M, Kovar J, Jir-sa M, Lukas M, Vitek L (2008) CYP7A1 promoter polymorphism -203 A>C affects bile salt synthesis rate in patients after ileal resection. J Lipid Res 49 2664-2667... 

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