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Cholesterol is excreted from the body via the bile either in the unesterified form or after conversion into bile acids in the liver. Coprostanol is the principal sterol in the feces; it is formed from cholesterol by the bacteria in the lower intestine.

Bile Acids Are Formed from Cholesterol

The primary bile acids are synthesized in the liver from cholesterol. These are cholic acid (found in the largest amount in most mammals) and chenodeoxycholic acid (Figure 26–7). The 7α-hydroxylation of cholesterol is the first and principal regulatory step in the biosynthesis of bile acids and is catalyzed by cholesterol 7α-hydroxylase, a microsomal cytochrome P450 enzyme (see Chapter 12) designated CYP7A1. A typical monooxygenase, it requires oxygen, NADPH, and cytochrome P450. Subsequent hydroxylation steps are also catalyzed by monooxygenases. The pathway of bile acid biosynthesis divides early into one subpathway leading to cholyl-CoA, characterized by an extra α-OH group on position 12, and another pathway leading to chenodeoxycholyl-CoA (Figure 26–7). A second pathway in mitochondria involving the 27-hydroxylation of cholesterol by the cytochrome P450 sterol 27-hydroxylase (CYP27A1) as the first step is responsible for a significant proportion of the primary bile acids synthesized. The primary bile acids (Figure 26–7) enter the bile as glycine or taurine conjugates. Conjugation takes place in liver peroxisomes. In humans, the ratio of the glycine to the taurine conjugates is normally 3:1. In the alkaline bile (pH 7.6-8.4), the bile acids and their conjugates are assumed to be in a salt form—hence the term “bile salts.”

FIGURE 26–7

Biosynthesis and degradation of bile acids. A second pathway in mitochondria involves hydroxylation of cholesterol by sterol 27-hydroxylase. *Catalyzed by microbial enzymes.

Primary bile acids are further metabolized in the intestine by the activity of the intestinal bacteria. Thus, deconjugation and 7α-dehydroxylation occur, producing the secondary bile acids, deoxycholic acid, and lithocholic acid.

Most Bile Acids Return to the Liver in the Enterohepatic Circulation

Although products of fat digestion, including cholesterol, are absorbed in the first 100 cm of small intestine, the primary and secondary bile acids are absorbed almost exclusively in the ileum, and 98% to 99% is returned to the liver via the portal circulation. This is known as the enterohepatic circulation (Figure 26–6). However, lithocholic acid, because of its insolubility, is not reabsorbed to any significant extent. Only a small fraction of the bile salts escapes absorption and is therefore eliminated in the feces. Nonetheless, this represents a major pathway for the elimination of cholesterol. Each day the pool of bile acids (about 3-5 g) is cycled through the intestine 6 to 10 times and an amount of bile acid equivalent to that lost in the feces is synthesized from cholesterol, so that a pool of bile acids of constant size is maintained. This is accomplished by a system of feedback controls.

Bile Acid Synthesis Is Regulated at the CYP7A1 Step

The principal rate-limiting step in the biosynthesis of bile acids is at the CYP7A1 reaction (Figure 26–7). The activity of the enzyme is feedback regulated via the nuclear bile acid-binding receptor, farnesoid X receptor (FXR). When the size of the bile acid pool in the enterohepatic circulation increases, FXR is activated, and transcription of the CYP7A1 gene is suppressed. Chenodeoxycholic acid is particularly important in activating FXR. CYP7A1 activity is also enhanced by cholesterol of endogenous and dietary origin and regulated by insulin, glucagon, glucocorticoids, and thyroid hormone.

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