Taurocholate synthesis

The intestinal absorption of dietary cholesterol esters occurs only after hydrolysis by sterol esterase steryl-ester acylhydrolase (cholesterol esterase, EC 3.1.1.13) in the presence of taurocholate [113][114], This enzyme is synthesized and secreted by the pancreas. The free cholesterol so produced then diffuses through the lumen to the plasma membrane of the intestinal epithelial cells, where it is re-esterified. The resulting cholesterol esters are then transported into the intestinal lymph [115]. The mechanism of cholesterol reesterification remained unclear until it was shown that cholesterol esterase EC 3.1.1.13 has both bile-salt-independent and bile-salt-dependent cholesterol ester synthetic activities, and that it may catalyze the net synthesis of cholesterol esters under physiological conditions [116-118], It seems that cholesterol esterase can switch between hydrolytic and synthetic activities, controlled by the bile salt and/or proton concentration in the enzyme s microenvironment. Cholesterol esterase is also found in other tissues, e.g., in the liver and testis [119][120], The enzyme is able to catalyze the hydrolysis of acylglycerols and phospholipids at the micellar interface, but also to act as a cholesterol transfer protein in phospholipid vesicles independently of esterase activity [121],... 

Bile salts (or bile acids) are polar derivatives of cholesterol and constitute the major pathway for the excretion of cholesterol in mammals. In the liver, cholesterol is converted into the activated intermediate cholyl CoA which then reacts either with the amino group of glycine to form glycocholate (Fig. 3a), or with the amino group of taurine (H2N-CH2-CH2-S03", a derivative of cysteine) to form taurocholate (Fig. 3b). After synthesis in the liver, the bile salts glycocholate and taurocholate are stored and concentrated in the gall bladder, before release into the small intestine. Since they contain both polar and nonpolar... 

Protein synthesis Glycogen synthesis Lactate uptake Amino acid uptake Glutaminase Glycine oxidation Ketoisocaproate oxidation Acetyl-CoA carboxylase Urea synthesis from amino acids Glutathione (GSH) efflux Taurocholate excretion into bile Actin polymerization Microtubule stability Lysosomal pH... 

In addition to taurocholic acid in the bile, free taurine is excreted in the urine. At times of low intake or when synthesis is impaired, for excunple by vitamin Be deficiency, the renal tubulcu resorption of taurine is incretised, thus reducing urinary losses. 

Derivation From glycocholic and taurocholic acids in bile organic synthesis. 

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 mechanism of the inhibition of the HMG-CoA reductase by bile adds shown in Fig. 14 is a matter of controversy. Weis and Dietschy did not observe any influence of taurocholate on cholesterol synthesis in bile fistula rats fed a cholesterol-free diet, and concluded that the inhibitory effect of bile acids on cholesterol synthesis may be related to the increased absorption of cholesterol by the presence of bile acids in the intestine [247]. However, Hamprecht et al. were able to demonstrate a reduction of HMG-CoA reductase activity in lymph fistula rats infused with cholate [248]. Results by Shefer et al. also indicate that bile acids inhibit HMG-CoA reductase directly [212]. It seems likely that the inhibitory effect of the bile acids on HMG-CoA reductase may involve both direct and indirect effects. It was recently established that the stimulation of HMG-CoA reductase activity in response to treatment with cholestyramine is associated with an increase of the specific mRNA [258]. 

Since plasma lipoprotein cholesterol must be the major substrate for bile acid biosynthesis under conditions when the rate of hepatic synthesis of cholesterol is low, regulation of the uptake of lipoprotein cholesterol by the hepatocytes should be of importance not only for the rate of cholesterol synthesis but also for the activity of cholesterol 7a-hydroxylase. It should be mentioned that bile acids are included among the different factors known to be able to modulate the receptor-mediated uptake of cholesterol by the apo-B, E or LDL receptor. The apo-B, E receptor can thus be induced to high levels by treatment with a bile acid sequestrant ]259]. Angelin et al. have shown that preparation of a bile fistula in adult dogs markedly induced the expression of the apo-B, E receptor and that the binding of this receptor could be almost totally abolished by reinfusion of taurocholate [260]. 

Cyprinol sulfate was first found in bile of the eel. Conger myriaster, the principal bile salts of which are taurocholate and taurochenodeoxycholate [26], 5j8-Cyprinol sulfate was later found in the bile of some species of frogs as their principal bile salt [9,18,19,27], and was also detected in bile of some fishes as their minor bile salt [28,29], The structure of 5 8-cyprinol was determined as 5)8-choles-tane-3a,7a,12a,26,27-pentol by direct comparison with the synthetic sample prepared by Hoshita et al. before its isolation from natural sources [30], Partial synthesis of 5)8-cyprinol was also reported by Haslewood and Tammar [29],... 

Growing chicken128 and hens129 utilize sulphate sulphur for cystine synthesis. Biological radio-tracer experiments130 with Na235S04 (10 fiCi) have shown that over 65% of the 35S administered to a 24-hour-old embryo is incorporated into taurine of the chick. No radioactive cystine, methionine or cysteic acid was detected in the hydrolysate obtained from the embryo and only a small portion of total taurine-35S occurs as taurocholic acid. The embryo is unable to utilize sulphate sulphur for cystine synthesis. 

Studies with radioactive glycocholate or taurocholate demonstrated a virtual absence of the enterohepatic circulation of bile acids in patients with jejunotransversocolostomy (77). The small amount of absorbed bile acids contained some deconjugated cholate and deoxycholate (which had been reconjugated in the liver), indicating a rapid bacterial action during an apparently fast intestinal passage. Under these conditions, steatorrhea is apparently not solely due to bile salt deficiency induced impairment of micelle formation, but reduced absorptive area may play an important contributory role. No direct measurement of bile acid synthesis by fecal determination has been performed in this condition. 

The demonstration by Bergstrom et al. (4,5) in 1953 of the conversion of deoxycholic acid to taurocholic acid in the rat in vivo and by rat liver slices paved the way for studies on 7a-hydroxylation and conjugation of bile acids. The early work on the synthesis of bile acid conjugates in vitro utilized slices or homogenates of rat and human liver, and the enzymatic reaction was followed by the incorporation of radioactivity from carboxyl- C-labeled bile acids into the corresponding taurine and glycine conjugates (6,7). The... 

In contrast, in ileal absorptive disorders, Garbutt et al. (38) observed an increase in G T ratios of both cholate and deoxycholate, which was attributed to a decrease in enterohepatic recirculation of taurocholate and deoxycholate. It is also interesting to note that a selective conjugation of cholic acid with L-ornithine could be induced in the rat and guinea pig liver by the injection of a toxic capsular polysaccharide of Klebsiella pneumoniae (39). Partial hepatectomy has also been shown to result in a shutdown in the hepatic synthesis of glycine conjugates of bile acids (40). 

Elliott, W. H. The enzymic synthesis of taurocholic acid a qualitative study. Biochem. J. 62, 433 (1956). 

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