Glycocholate synthesis

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... 

A. This compound is the bile salt glycocholic acid. During its synthesis, the ring structure of cholesterol is hydroxylated and reduced, and the side chain is oxidized and conjugated with... 

Derivation From glycocholic and taurocholic acids in bile organic synthesis. 

Synthesis of the Bile Acid Cholic Acid (a) and the Bile Salt Glycocholate (b). 

After cholesterol is formed, it can be converted to other steroids of widely varying physiological function. The smooth ER is an important site for both the synthesis of cholesterol and its conversion to other steroids. Most of the cholesterol formed in the liver, which is the principal site of cholesterol synthesis in mammals, is converted to bile acids, such as cholate and glycocholate (Figure 21.30). These compounds aid in the digestion of lipid droplets by emulsifying them and rendering them more accessible to enzymatic attack. 

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. 

It is difficult to study hormonal factors regulating bile acid synthesis in intact animals because effective stimuli are counteracted by homeostatic mechanisms. Recently (36), effects of cortisone on bile acid production and biosynthesis were studied using the isolated, perfused rabbit liver (37), which offers a less complex system in which bile is easily sampled. When the donor rabbits were pretreated with cortisone acetate (3 mg/kg, intramuscularly) for 3 days, secretion of glycocholate during a 2.5-hr perfusion increased two-to threefold. The incorporation of acetate-1- C into bile acids was likewise increased, suggesting that part of the stimulatory effect was due to an increase in bile acid biosynthesis. Biliary cholesterol concentration (but not de novo... 

Mosbach et al, (35) have used cholestyramine to confirm that the la-hydroxylation of cholesterol is the rate-limiting step in bile acid synthesis. Because of the loss of cholesterol from the enterohepatic circulation, there is a marked increase in cholesterol synthesis during administration of cholestyramine to rats (27) or man (36). Mosbach et aL, using perfused rabbit liver, showed that the biliary content of glycocholic acid rose from 0.34 to 3.3 mg, while the content of glycodeoxycholic acid fell from 7.4 to 3.7 mg. The conversion of radioactive acetate, mevalonate, or cholesterol to bile acids was increased from five- to twentyfold, but the conversion rate of 7a-hy-droxycholesterol to cholic acid was unchanged. The formation of 7a-hy-droxycholesterol from cholesterol is enhanced by treatment with cholestyramine (37,38). 

Fig. 4. Increase of initial rate of synthesis of taurochoiic ami glycocholic acids on addition of L-fraction protein to the incubation medium. — , Synthesis for C-min jtc incubation time ------synthesis for 10-minuto inoubation time.

The mechanism,s behind the changes in the synthesis of taurocholic and glycocholic acids in human liver in patients with obstructive jaundice ivas analyzed by Schersten (1967a,b). The following possible explanations for a lower capacity of the synthesis of bile acid conjugates or for an altered conjugation pattern in such cases were provioundcd. 

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